VEGF TKI Research Articles

17 CDK4/6 inhibition with Abemaciclib in in patients (pts) with previously treated advanced renal carcinoma (RCC)

Abstract Background Preclinical data suggests rationale for CDK4/6 alone and in combination with HIF-2 inhibitors; single agent activity for CDK4/6 inhibitors in RCC has not been reported. Abemaciclib is an oral CDK4/6 inhibitor approved in combination with hormonal therapy for metastatic breast cancer. In our phase 1b clinical trial (NCT04627064), we investigated the safety and clinical efficacy of abemaciclib monotherapy in pts with advanced pretreated RCC with clear cell component. Methods In this single center trial, adult pts with advanced RCC with a clear cell component and ECOG status of ≤1 progressing after at least one prior regimen including immunotherapy and a VEGF TKI received abemaciclib 200 mg twice daily in 4-week cycles until progression or unacceptable toxicity. Primary objective was to evaluate the objective response rate (ORR) of abemaciclib with secondary endpoint of safety. First imaging was performed after 2 cycles. Response assessed per RECIST 1.1 and toxicity per CTCAE v5.0. Results 11 pts (10 clear cell RCC and 1 translocation RCC) were enrolled between 12/31/2020 and 10/03/2023. Median age was 62 years (range 54-68) with 18% (n=2) showing sarcomatoid features. 73% (n=8) had IMDC intermediate risk disease and one patient had translocation RCC (tRCC) with a clear cell component. Median number of prior therapies was 4 (range 1-9). Seven patients received 2 cycles and 4 patients received < 2 cycles. ORR was 0% (0/11; 8 progressive disease, 1 stable disease in tRCC stopping for clinical progression, 2 pts not evaluable with clinical progression). 27% (n=3) experienced grade ≥3 treatment-related adverse events (diarrhea n=1, nausea n=1, neutropenia n=1). Conclusions In pts with heavily pretreated RCC, abemaciclib had manageable toxicity profile but no clinically meaningful activity as monotherapy. This data will offer important insight into interpretation of results for ongoing trials exploring CDK4/6 inhibition in combination with HIF-2 inhibitors.

FDA analysis of immune checkpoint inhibitors in combination with vascular endothelial growth factor tyrosine kinase inhibitors in the second-line treatment of patients with advanced non-small cell lung cancer.

8595 Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 in combination with platinum-based chemotherapy is standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). The majority of these patients progress and there remains a high unmet medical need in the second-line setting given the limited FDA approved available therapies. The ICI plus vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) combination, successful across several tumor types, was studied in NSCLC as a potential treatment option. Methods: The FDA identified 3 randomized trials conducted between June 2019 and August 2023, comparing the combination regimen ICI plus VEGF TKI to docetaxel in patients with advanced NSCLC who had progressed on both platinum-based chemotherapy and an ICI. All 3 trials were publicly reported to have not met their primary endpoint. Topline results for key efficacy and safety outcomes from each of the 3 trials were provided by the commercial sponsors. Results: 1317 total patients across 3 trials (LEAP-008, SAPPHIRE and CONTACT-01) were randomized to receive either an ICI plus VEGF TKI or docetaxel. The results are presented (Table). Efficacy parameters demonstrated similar results across trials between arms. There was no clear signal that the combination is more effective than single agent docetaxel. Safety parameters across trials consistently demonstrated higher rates of toxicity with the combination. Conclusions: ICI plus oral VEGF TKI combinations have not demonstrated an advantage over docetaxel in randomized trials of patients with advanced NSCLC. In 2 of the 3 trials, response rate data did not demonstrate superior efficacy compared to docetaxel. Additionally, any observed PFS benefit was small in magnitude. The relatively low efficacy, in combination with the additive toxicity of the regimen, may curtail a potential OS benefit. There remains a high unmet medical need in this patient population and further analysis is necessary to explore potential NSCLC subgroups which may derive benefit. [Table: see text]

BP elevation does not increase risk of MACE during VEGF TKI therapy

BP elevation does not increase risk of MACE during VEGF TKI therapy

OPtimal Treatment by Invoking biologic clusters in renal cell carcinoma (OPTIC RCC)

Abstract Background The first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) includes immune oncology (IO) based combination therapy. The current standard includes a PD-1 inhibitor plus either an anti-CTLA-4 inhibitor (IO/IO) or an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGF TKI) (IO/TKI). Currently, there is no evidence to guide a physician’s choice between an IO/IO versus an IO/TKI combination. The phase III IMmotion 151 trial performed RNA-seq from 823 ccRCC tumors and established seven biologically distinct gene expression clusters of ccRCC (Motzer and Rini et al., Cancer Cell 2020). The seven clusters showed differential responses to immune checkpoint inhibitor and may serve as a predictive biomarker to select clusters to assign patients with mccRCC to either an IO/IO (ipilimumab/ nivolumab) or an IO/TKI (nivolumab/cabozantinib) regimen. Methods Patients diagnosed with mccRCC without prior systemic therapy (including in the neoadjuvant or adjuvant setting) and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. RNA-seq will be performed on metastatic tumor specimens and used to assign tumor clusters. Patients with cluster 1/2 tumors will be assigned to the nivolumab/cabozantinib arm. Patients with cluster 4/5 tumors will be assigned to the ipilimumab/nivolumab arm. Cluster 3/6/7 will be excluded. The primary endpoint is overall response rate (ORR) per RECIST 1.1. Key secondary endpoints include progression-free survival, depth of response >80%, and rate of immune-related adverse events (irAEs). The hypothesis is that use of tumor clusters to assign front-line therapy to either nivolumab/cabozantinib or ipilimumab/nivolumab will lead to a 20% greater ORR compared to unselected historical controls in CheckMate 9ER (ORR 55%) or CheckMate 214 (ORR: 40%). This trial adopts Simon’s MiniMax two-stage design (power: 80%, one-sided alpha: 0.1). For the nivolumab/cabozantinib arm, stage I will enroll 12 eligible patients. If there are 7 or more responders in the first 12 patients, stage II will enroll an additional 14 patients (n=26). For the ipilimumab/ nivolumab arm, stage I will enroll 16 eligible patients. If there are 7 or more responders in the first 16, stage II will enroll an additional 12 patients (n=28). The primary endpoint will be met if there are 15 or more responders (ORR>60%). This trial is open and enrolling with 12 patients on study at Vanderbilt University Medical Center and additional sites to open including UT Southwestern, City of Hope, University Hospitals Seidman Cancer Center, and Cleveland Clinic. This trial is funded by the Department of Defense Kidney Cancer Research Program Clinical Trial Award (W81XWH-22-1-1033) (NCT05361720). CDMRP DOD Funding: yes

Multi-centre review of systemic anti-cancer prescribing patterns and treatment drop off rates in the United Kingdom 2018-2021.

689 Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved over recent years with several systemic anti-cancer therapies (SACT) licensed across different lines of treatment. There is ongoing discussion amongst oncology professionals about how best to optimise treatments in terms of sequencing to maximise the potential number of lines or to give the best treatments first. A previous south-west UK audit was completed in 2021 reviewing the drop off rates across 5 UK sites identifying that 69% of patients were able to receive second line therapy and 34% were able to receive third line therapy. Methods: In this study we conducted retrospective analysis of all patients who commenced treatment with SACT for mRCC between 1st January 2018 and 30th June 2021 in 18 centres across the 4 nations of the United Kingdom. All NHS reimbursed treatment options including the COVID interim treatment guideline options were included. Patients who received SACT as part of a clinical trial were also included. Patients who continued on their respective lines of treatment were censored. We also identified patients who had been on a period of active surveillance before staring SACT in this cohort. Results: 1549 patients (71% male: 29% female) were included. IMDC subgroup patients included 21.6% favourable, 52.3% intermediate, 25.1% poor and 1% unavailable. 9.1% of patients had been on active surveillance before starting SACT – defined as a period of longer than 3 months from mRCC diagnosis to starting SACT. Of those patients that started SACT 60.5% of eligible patients had 2nd line therapy, 25.3% had 3rd line, 7.2% received 4th line therapy and only 1% had 5th line therapy. In the 1st line setting 58.9% received single agent VEGF TKI, 24.5% received combination ipilimumab and nivolumab (IO-IO) immunotherapy, 14 % received IO/ VEGF TKI combination and 2.6% received other/trial treatment. The single agent VEGF TKI ratio for 1st line SACT declined year by year with rising IO-IO and IO/VEGF TKI combination ratios seen. In the second- and third-line settings cabozantinib (33.2% 2nd line and 44.4% 3rd line) and nivolumab (32.8% 2nd line and 22.6% 3rd line) were the most common options. Disease progression or death was the most common cause of SACT discontinuation amounting to 57.4%, 62.5% and 79% of SACT cessation in the 1st, 2nd and 3rd lines respectively. Treatment toxicity SACT discontinuation rates were 22.8%, 21.4% and 10.9% for 1st, 2nd and 3rd lines respectively. Conclusions: These results suggest that with more treatment options available, including combination/immunotherapy therapies, more patients are able to receive second- and third-line therapies. That said there remains significant drop off rates mostly driven by disease progression that would support the use of our most effective therapies in the upfront setting.

The effect of anti-cancer therapy on immunological response to COVID-19 vaccination.

319 Background: The efficacy of SARS-COV-2 vaccination has been demonstrated in healthy individuals. Immune responses are less well characterised in cancer patient groups, especially those receiving anticancer therapy (e.g. immune therapy, chemotherapy and targeted therapies. We aim to assess the immune response to the SARS-COV-2 vaccination in patients with solid organ cancer on different systemic anti-cancer therapies. Methods: All patients received 2 doses of COVID-19 mRNA vaccination as part of the UK National vaccination programme; with the second booster dose administered within 12 weeks of the first dose. All patients received either BNT162b2 (Pfizer/BioNTech) or ChAdOx1 S (AstraZeneca) vaccines. Sequential serum samples were collected pre-booster dose vaccination (baseline/within -30 days) and after second dose SARS-COV-2 vaccination, at 14-35 days and 36-63 days. Presence and titres of serum Anti-SARS-CoV-2 Spike protein (S) antibody titres were measured. Seroconversion is defined as a response ≥0.8 U/ml, and maximum response to Anti-S is defined as ≥250 U/ml. Responses were measured in 3 patient groups according to the type of anti-cancer therapy: chemotherapy (CHT group), immune therapy (IO group) and targeted therapies, mainly VEGF TKI (TT group). Results: Overall, 61 patients were recruited: 45.9%(28/61) in CHT group, 32.8% (20/61) in IO group and 21.3% (13/61) in the TT group. Baseline characteristics were comparable between patient groups. In response to the booster dose vaccination at 14-35 days, the number of patients who seroconverted was 79.3% (23/29), 94.7% (18/19) and 84.6% (11/13) in the CHT, IO and TT groups, respectively. At this same time point, 51.7% (15/29) in the CHT group achieved maximum anti-S titre levels (≥250 U/ml), compared with 78.9% (15/19) of patients in IO group and 69.2% (9/13) of patients in TT group. All 3 groups demonstrated a significant increase in Anti-S antibodies at 14-35 days after second dose vaccine when compared to pre-booster serum levels, with the largest increase seen in the IO group with a mean Anti-S increase of 149.1 U/ml (SD±105.0, p < 0.0001) followed by the TT group mean increase 120.2 U/ml (SD ±110.8, p < 0.01) and the CHT group, mean increase 83.0 U/ml (SD ±108.4, p < 0.001). Anti-S antibody levels were sustained at 36-63 days post-booster across all groups. However only IO patients had a sustained immune response to vaccination, with median Anti-S titres level of ≥250 U/ml and a significant drop was seen in the CHT group (median Anti-S level 138, p < 0.05). Conclusions: Anti-S titres increase following vaccination in all 3 groups but remain most sustained in the IO group at 36-63 days post-vaccination. Chemotherapy and other targeted therapy treated patients may benefit from early COVID-19 vaccine boosters, compared to patients receiving immune therapy.

A multicenter real-world study reviewing systemic anticancer treatment choices and drop off rates between treatment lines for metastatic renal cell carcinoma in the United Kingdom: In the immunotherapy era.

358 Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved over the last few years with several systemic anti-cancer therapies (SACT) licensed across different lines of treatment. A previous real world study in the UK had demonstrated a significant attrition rate between each line of therapy suggesting less than half of patients who received first line SACT then received second line therapy and less than a fifth of first line SACT patients reach third line. Methods: We conducted a retrospective analysis of all patients treated between January 2018 and end of June 2021 to see if advancement in treatment options had impacted on the drop-off rates. Data was collected from 5 UK sites. Patients were identified from electronic SACT database. All reimbursed treatment options including the COVID interim treatment guidelines options were included. Patients who received SACT as part of a clinical trial were also included. Patients who remained on the respective lines of treatment were censored. Results: Data for 515 patients (372 male: 143 female) who received first-line SACT for mRCC were included in the analyses. IMDC prognostic groups were 103 favourable, 236 intermediate, 127 poor (49 not available). On progression 69% of patients were able to receive second-line therapy and 34% were able to receive third-line therapy. Of the 515 first-line therapies, 24% of patients received frontline ipilimumab and nivolumab, 10% received TKI and IO combination and 63% received single agent VEGF TKI. Second-line nivolumab or cabozantinib (43% and 40% respectively) were the most commonly prescribed options. Third-line cabozantinib 61% and nivolumab 16% remain the most used options. Across all lines of therapy progressive disease was the primary reason for discontinuation. 5% switched treatment due to toxicity. Conclusions: These results suggest that, with more treatment options available, including combination/ immunotherapy therapies, more patients are able to receive second and third-line therapies. Despite this, nearly one third of patients only receive one line of treatment which highlights the need to deliver the most efficacious treatments first to optimise patient outcomes. Moreover, single agent TKI was the most commonly used first-line SACT despite advances in the management pathway. Data analysing the impact of COVID on treatment selection will be presented.[Table: see text]

KEYNOTE-B61: Open-label phase 2 study of pembrolizumab in combination with lenvatinib as first-line treatment for non-clear cell renal cell carcinoma (nccRCC).

TPS4595 Background: Most RCCs contain clear cell histology; the remainder of cases are summarized as nccRCC. nccRCC is a heterogeneous group of tumors and, with advanced metastases, survival is uniformly worse than with clear cell RCC (ccRCC) because of the aggressiveness of these cancers and a lack of effective systemic treatment options. Because data are limited for patients with nccRCC, the role of various agents in the treatment of nccRCC is poorly defined and there is no standard of care; treatment guidelines recommend clinical trials as preferred strategy. Inhibition of the PD-1/PD-L1 pathway is an effective treatment option for nccRCC, and pembrolizumab monotherapy has shown efficacy with an acceptable safety profile as first-line treatment. The VEGF TKI lenvatinib has also shown efficacy with a tolerable safety profile as combination therapy with everolimus for nccRCC. Also, in the phase 3 KEYNOTE-581 study (NCT02811861), the combination of lenvatinib + pembrolizumab as first-line therapy showed antitumor activity in patients with metastatic ccRCC, suggesting this combination might be an excellent therapeutic option for nccRCC. The phase 2, open-label, single-arm, KEYNOTE-B61 study (NCT04704219) is being conducted to evaluate pembrolizumab in combination with lenvatinib as first-line treatment for nccRCC. Methods: Patients with centrally confirmed nccRCC, locally advanced/metastatic measurable disease per RECIST v1.1 per blinded independent central review (BICR), no prior systemic therapy for nccRCC, and KPS score ≥70 will be enrolled. Approximately 152 patients will receive pembrolizumab 400 mg every 6 weeks and lenvatinib 20 mg once daily. Pembrolizumab treatment will continue for up to approximately 2 years or until a discontinuation criterion is met (disease progression, unacceptable toxicity, or withdrawal of consent); lenvatinib treatment can continue beyond 2 years or until one of the same discontinuation criterion is met. Participants who discontinue one of the treatments can continue to receive the other treatment as monotherapy. A second-course treatment phase is available for patients who meet specific criteria. CT/MRI will be performed at 12 weeks from the start of treatment, every 6 weeks until week 54, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and graded using CTCAE, version 5.0, guidelines. The primary end point is objective response rate based on RECIST v1.1 per BICR. Secondary efficacy end points for this study are clinical benefit rate, disease control rate, duration of response, progression-free survival, overall survival, and safety. Tertiary/exploratory end points are biomarker analysis and association with clinical response/disease etiopathogenesis. Clinical trial information: NCT04704219.

The very favorable metastatic renal cell carcinoma (mRCC) risk group: Data from the International Metastatic RCC Database Consortium (IMDC).

339 Background: The IMDC criteria have been used as a prognostic tool for patients with mRCC receiving single agent VEGF-targeted drugs, and more recently combination immuno-oncology (IO) +/- VEGF-targeted agents, which improve outcomes over VEGF TKI monotherapy. We sought to identify a subset of patients with very favorable outcomes, for which less intensive therapy might be considered. Methods: Utilizing the IMDC dataset, 1638 patients with IMDC favorable risk disease received first-line systemic therapy. Patients were randomly selected in a 2:1 ratio to the training and testing sets, stratified by year of systemic therapy initiation. Multivariable Cox regression estimated prognostic factors for overall survival (OS). Results: Median age was 63 (range 21-95) years and 98% had received prior nephrectomy. First-line systemic therapy consisted of targeted therapy (91%), IO-combination regimens (8%), or other (1%). From the training data, three variables (primary diagnosis to systemic therapy <3 vs ≥3yr; Karnofsky Performance Status 80 vs >80; presence of brain, liver, or bone metastasis) significantly predicted for OS in the multivariable model (hazard ratio 1.4~1.5, p-values<0.05). The model had similar performance in the test dataset (C-index=0.64). Using the 3 included risk factors, patients were classified to very favorable risk (0 risk factors, 29% of patients) or favorable risk disease (≥1 risk factors, 71% of patients). Clinical outcomes for the two risk groups are presented in the table below. Conclusions: We identified a very favorable risk group in the IMDC criteria in RCC patients treated with first-line therapy. External validation including populations receiving IO containing therapies is ongoing. [Table: see text]

PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).

TPS366 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN (A031203) trials. Combination immunotherapy with VEGF therapies has shown benefit over sunitinib in the JAVELIN 101 and KEYNOTE 426 trials. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter phase III trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1 mg/kg and NIVO 3 mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480 mg IV every 4 weeks; pts with progression of disease (PD) switch to CABO 60 mg oral daily; pts with non-CR/non-PD are randomized to NIVO 480 mg IV every 4 weeks versus NIVO 480 mg IV every 4 weeks with CABO 40 mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include progression-free survival, 12-month CR rate, overall response rate based on RECIST 1.1 and iRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR, tissue-based and plasma-based biomarkers will be assessed. Updated enrollment through January 2021 will be presented. Clinical trial information: NCT03793166 .

PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).

TPS5100 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN (A031203) trials. Combination immunotherapy with VEGF therapies has shown benefit over sunitinib in the JAVELIN 101 and KEYNOTE 426 trials. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter phase 3 trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1 mg/kg and NIVO 3 mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, Karnofsky performance status > 70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480 mg IV every 4 weeks; pts with progression of disease (PD) switch to CABO 60 mg oral daily; pts with non-CR/non-PD are randomized to NIVO 480 mg IV every 4 weeks versus NIVO 480 mg IV every 4 weeks with CABO 40 mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include progression-free survival, 12-month CR rate, overall response rate based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR, tissue-based and plasma-based biomarkers will be assessed. Updated enrollment through May 2020 will be presented. Clinical trial information: NCT03793166 .

Treatment for Recurrent Differentiated Thyroid Cancer: A Canadian Population Based Experience.

Introduction: Management of recurrent differentiated thyroid cancer (DTC) may include surgery, radioactive iodine (RAI), and external beam radiotherapy (EBRT). Systemic therapy may also be offered for RAI-refractory DTC. The study objective was to review patterns of practice in British Columbia (BC) for treatment of recurrent DTC, assess rates of RAI-refractory disease, and evaluate outcomes.Methods: BC Cancer provides cancer care to a population of 4.6 million. A retrospective review of all patients with DTC stage I-IVB disease referred to BC Cancer from 2009 to 2013 was conducted. Patient and DTC characteristics, locoregional and distant recurrence, surgical management, RAI, EBRT, and systemic therapy details were retrospectively collected. Relapse-free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were calculated using the Kaplan-Meier method.Results/Discussion: Some 1062 DTC patients were identified. Median follow-up was 4.1 years. Baseline characteristics: female 74%, median age 50, papillary/follicular/Hurthle cell 92%/6%/2%. Stage at presentation: I 60%, II 8%, III 22%, IVA/IVB 10%. Locoregional and/or distant recurrence occurred in 136 patients (13%). Locoregional recurrence (n=118) was treated with surgery +/- RAI or EBRT 48%, RAI +/- EBRT 40%, EBRT alone 1%, 11% were observed without treatment. Some 27 patients had a second cancer recurrence. Some 37 patients (3%) developed distant metastatic disease and common sites of distant metastases were: lung 76%, bone 30%, and liver 8%. Some 27 cases (2%) were deemed RAI-refractory. Some six patients (0.6%) received systemic therapy with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). Five-year RFS was calculated to be 82%, OS 95%, and DSS 98% for the study population.Conclusions: In our population-based study cohort, 87% of patients were rendered disease-free by primary disease management. Multi-modality treatment of locoregional recurrence facilitated disease-free status in the majority of patients (67%). RAI-refractory disease developed in 2% of patients and despite a significant number of metastatic recurrences, only a small number of patients received systemic therapy.

Outcomes after first-line therapy for immune/immune or immune/VEGF combinations.

706 Background: The introduction of first line immune combination or immune/VEGF therapy in metastatic renal cancer has changed treatment landscape. Here we compare outcomes of these combinations with patients treated with first line sunitinib. The focus is on the impact of subsequent treatments. Methods: This retrospective analysis was performed at Barts Cancer Institute for consecutive patients from April 2015 when front line immune therapy was first used at our institution. Only patients enrolled on reported prospective trials were included to avoid selection bias. Patients were treated with VEGF targeted therapy (n=35) (group V), PD-1 + CTLA4 (n=15) (group I/I) or a combination of PD-L1 + VEGF TKI inhibitor (n=29) (group I/V). The primary analysis focused on the proportion of patients who received second line therapy and their outcome. Results: 79 patients received first line therapy for clear cell RCC. IMDC good, intermediate and poor risk occurred in 27.8%, 60.8% and 11.4% respectively. Front line response rates for V, I/I and I/V groups were 34.3%, 46.7% and 65.5% and PFS in V, I/I and I/V groups were 11mo (95%CI 6-16), 18mo (95% CI 0-41) and 36mo (95% CI 13-59), respectively (P= 0.016). OS in the 3 groups were immature but not significantly different. Second line therapy occurred in 87.5%, 92.9% and 81.8% in the V, I/I and I/V groups respectively (in those who progressed after initial therapy). Second line response rate post first line V, I/I and I/V were 11%, 0% and 0% respectively as per RECIST 1.1. 63% of patients receiving VEGF front line therapy subsequently received immune therapy. 95% of patients receiving first line immune/immune or immune/VEGF combination therapy received VEGF therapy in the second line. Only 70% of patients who progressed on second line therapy got 3rd line therapy across all arms. Conclusions: Response rates after front line immune combination therapy are modest. The sequencing of PD-1 therapy after VEGF monotherapy appears particularly relevant in outcomes. A high proportion of patients are sequencing therapy and reaching third line which may help improve outcomes.

PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).

TPS760 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN trials. Combination immunotherapy with VEGF therapies have shown benefit in the JAVELIN 101 and KEYNOTE 426 trials over sunitinib. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter, phase 3 trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1mg/kg and NIVO 3mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, IMDC intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480mg IV every 4 weeks, pts with progression of disease (PD) switch to CABO 60mg oral daily, and pts with non-CR/non-PD are randomized to NIVO 480mg IV every 4 weeks versus NIVO 480mg IV every 4 weeks with CABO 40mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS rate will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include PFS, 12-month CR rate, ORR based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR and association of IL-6 with treatment benefit will be assessed. Other tissue-based and plasma-based biomarkers are planned. Updated enrollment will be presented. Clinical trial information: NCT03793166.

PDIGREE: An adaptive phase 3 trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).

TPS4596 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN trials. Combination immunotherapy with VEGF therapies have shown benefit in the JAVELIN 101 and KEYNOTE 426 trials over sunitinib. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter, phase 3 trial (Alliance A031704, PDIGREE), pts will start treatment with induction IPI 1mg/kg and NIVO 3mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, IMDC intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) will undergo maintenance NIVO 480mg IV every 4 weeks, pts with progression of disease (PD) will switch to CABO 60mg oral daily, and pts with non-CR/non-PD will be randomized to NIVO 480mg IV every 4 weeks versus NIVO 480mg IV every 4 weeks with CABO 40mg oral daily. Randomization will be stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS rate will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include PFS, 12-month CR rate, ORR based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR and association of IL-6 with treatment benefit will be assessed. Other tissue-based and plasma-based biomarkers are planned. Enrollment will begin this year. Support from UG1CA189823, U24CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03793166.

First-line (1L) immuno-oncology (IO) combination therapies in metastatic renal cell carcinoma (mRCC): Preliminary results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

584 Background: In mRCC, ipilimumab and nivolumab (ipi-nivo) is a 1L treatment option. Recent data have also shown efficacy of 1L PD(L)1-VEGF (PV) inhibitor combinations. The efficacy of these two strategies has not been compared. Methods: Using the IMDC dataset, patients (pts) treated with any 1L PV combination were compared to those treated with ipi-nivo. Multivariable Cox regression analysis was performed to control for imbalances in IMDC risk factors. Results: 164 pts received 1L IO combination therapy: 104 treated with PV combinations and 60 with ipi-nivo. Baseline characteristics and IMDC risk factors were comparable between groups (Table). When comparing PV combinations vs ipi-nivo, 1L response rates (RR) were 30% vs 39% (p = 0.29), time to treatment failure (TTF) was 13.2 (95% CI 8.3-16.1) vs 8.5 months (95% CI 5.7-14.0, p = 0.31), and median overall survival (OS) was not reached (NR) (95% CI 19.7-NR) vs NR (95% CI 27.6-NR, p = 0.39). When adjusted for IMDC risk factors, the hazard ratio (HR) for TTF was 0.77 (95% CI 0.44-1.35, p = 0.36) and the HR for death was 0.94 (95% CI 0.33-2.71, p = 0.91). Similar results were seen when restricting the cohort to IMDC intermediate/poor risk pts only. In pts receiving subsequent VEGF TKI monotherapy, second-line (2L) RR (13% vs 45%, p = 0.07) and TTF (5.5 vs 5.4 months, p = 0.80) for PV combinations (n = 15) vs ipi-nivo (n = 20) were not significantly different. Conclusions: There does not appear to be a superior 1L IO combination strategy in mRCC, as PV combinations and ipi-nivo have comparable RR, TTF and OS. Although there is a trend towards differences in RR, there does not appear to be a significant difference in TTF for patients receiving 2L VEGF TKI therapy. [Table: see text]

Abstract CT081: Molecular correlates of differential response to Atezolizumab +/- Bevacizumab vs Sunitnib in a Phase II study in untreated metastatic renal cell carcinoma (RCC) patients

Abstract Background: The addition of bevacizumab (bev) to atezolizumab (atezo) has demonstrated enhanced anti-tumor immune responses in pts with solid tumors (Wallin 2016). In IMmotion150 (NCT01984242), a phase II trial that compared atezo+/-bev vs sunitinib (sun) in untreated mRCC, encouraging antitumor activity of atezo+bev vs sun was observed in PD-L1 expressing tumors. We performed integrated tumor genomic analyses to correlate molecular signatures with clinical outcomes. Methods: PD-L1 status on tumor infiltrating immune cells (IC) was assessed with the SP142 IHC assay (IC0, IC1, IC2/3) (n=297). Exploratory analyses included mutation evaluation by WES (n=170) and gene expression analysis by RNA-Seq (n=263). Established gene signatures at < median (low) or > median (high) expression levels representing T effector and IFNγ response (Teff) and angiogenesis (Ang) were evaluated in relation to PFS (RECIST v1.1 by independent review). Results: PFS was longer in PD-L1 IC2/3 and in PD-L1 IC1/2/3 in atezo+bev pts vs sun pts and in PD-L1 IC2/3 in atezo pts vs sun pts. High Teff signature expression was associated with PD-L1 IHC and longer PFS in atezo+bev pts vs sun pts. High Ang expression was associated with improved clinical activity in the sun arm; but not the atezo+bev arm. Atezo+bev had improved PFS vs sun in the Ang low subset. Additional data exploring association of high prevalence mutations with clinical outcome will be presented. Conclusions: These data indicate that the addition of bev to atezo may improve clinical benefit in patients with pre-existing anti-tumor immunity (as determined by high Teff score or PD-L1 IHC) compared to sun. Molecular profiles identified in these analyses suggest that prediction of differential outcomes to VEGF TKI and immunotherapy may be possible in front line mRCC. These results will be further explored in the ongoing phase III study IMmotion151 (NCT02420821). Atezo + Bev vs SunAtezo vs SunPFS HR (95% CI)PD-L1 IHC IC1/2/30.66 (0.41-1.07)0.97 (0.61-1.55)PD-L1 IHC IC2/30.36 (0.14-0.88)0.54 (0.23-1.28)Teff high0.55 (0.32-0.95)0.85 (0.50-1.43)Teff low1.41 (0.84-2.03)1.33 (0.76-2.33)Ang high1.36 (0.78-2.36)1.46 (0.81-2.60)Ang low0.58 (0.35-0.98)0.75 (0.45-1.25)PD-L1 IHC: IC1/2/3, ≥ 1% of TILs are PD-L1+; IC2/3, ≥ 5% of TILs are PD-L1+.Teff signature: CD8A, IFNG, PRF1, EOMES, PD-L1.Ang signature: VEGFA, KDR, ESM1, PECAM1, ANGPTL4, CD34. Citation Format: David McDermott, Mahrukh Huseni, Brian Rini, Robert Motzer, Michael Atkins, Berard Escudier, Dorothee Nickles, Zach Boyd, Shruthi Sampath, Jennifer Doss, Ning Leng, Christina Schiff, Daniel S. Chen, Gregg Fine, Thomas Powles, Priti S. Hegde. Molecular correlates of differential response to Atezolizumab +/- Bevacizumab vs Sunitnib in a Phase II study in untreated metastatic renal cell carcinoma (RCC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT081. doi:10.1158/1538-7445.AM2017-CT081

The effect of geography and the availability of second-line therapy on overall survival in a one-way crossover design study in renal cell carcinoma.

e16120Background: TIVO-1 was a randomized ph III study comparing tivozanib (T) to sorafenib (S) in patients with mRCC previously untreated with a VEGF TKI. The study was paired with a companion stu...

Comparative effectiveness of first-line (1st) VEGF TKI followed by second-line (2nd) therapy with either a VEGF TKI or an mTOR inhibitor in patients (pts) with metastatic renal cell carcinoma (mRCC).

e15589 Background: In the INTORSECT trial, not progression-free (PFS), but overall survival (OS) was higher with sorafenib vs. temsirolimus in 2nd setting after 1st sunitinib therapy in mRCC pts. H...

Comparative effectiveness of first-line VEGF TKI followed by second-line therapy with either a VEGF TKI or an mTOR inhibitor in patients with metastatic renal cell carcinoma.

495 Background: In the INTORSECT trial, not progression-free (PFS), but overall survival (OS) was higher with sorafenib vs. temsirolimus in 2nd setting after 1st sunitinib therapy. Here, we compare the PFS and OS between any vascular endothelial growth factor inhibitor (VEGF TKI) and mTOR inhibitors (mTORi) in 2nd setting in mRCC after progression on 1st VEGF TKI. Methods: Pts were identified from an institutional database. Survival estimates of PFS and OS were assessed from initiation of 2nd therapy by Kaplan-Meier methodology and stratified by the median PFS of the 1st therapy. Results: Of 142 pts, 66 received a VEGF TKI (n=24, 36%) or an mTORi (n=42, 64%) in 2nd setting. Pts and disease characteristics with corresponding outcomes are presented in the table. Conclusions: A trend for improved PFS and OS was found with 2nd therapy with a VEGF TKI over an mTORi. Longer OS with 2nd VEGF TKI was seen in those on 1st VEGF TKI <8 months suggesting that continued VEGF inhibition may be a reasonable strategy in these pts. Data need to be validated in a larger cohort. [Table: see text]