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LBA5 Background: Relapse after surgery for high-risk clear cell RCC (ccRCC) is associated with shortened life expectancy. Effective perioperative therapy to reduce this risk remains an unmet need. Adjuvant immune therapy is an attractive potential strategy for these pts. We conducted the KEYNOTE-564 trial to evaluate pembro vs placebo as adjuvant therapy for pts with RCC. Methods: KEYNOTE-564 is a phase III multicenter trial of pembro vs placebo in pts with histologically confirmed ccRCC, with intermediate-high risk (pT2, Gr 4 or sarcomatoid, N0 M0; or pT3, any Gr, N0 M0), high risk (pT4, any Gr, N0 M0; or pT any stage, any Gr, N+ M0), or M1 NED (no evidence of disease after primary tumor + soft tissue metastases completely resected ≤1 year from nephrectomy) (Leibovich et al, 2003; Fuhrman et al, 1982). Pts had undergone surgery ≤12 wks prior to randomization; had no prior systemic therapy; had ECOG PS 0 or 1. Study treatment was given for up to 17 cycles (≈1 yr). The primary endpoint was disease-free survival (DFS) per investigator assessment in all randomized pts (ITT population). Overall survival (OS) was a key secondary endpoint. Safety/tolerability were secondary endpoints, assessed in all treated pts. Results: Between Jun 30, 2017 and Sept 20, 2019, 994 pts were randomized 1:1 to pembro (n=496) or placebo (n=498). As of data cutoff date of Dec 14, 2020, median (range) follow-up, defined as time from randomization to data cutoff, was 24.1 (14.9−41.5) mo. No pts remain on study treatment. Baseline characteristics were generally balanced between arms. At first prespecified interim analysis, the primary endpoint of DFS was met (median not reached [NR] for both arms, HR 0.68, 95% CI 0.53−0.87; P=0.0010 [one-sided]). The estimated DFS rate at 24 mo was 77.3% with pembro vs 68.1% with placebo. Overall, DFS benefit was consistent across subgroups. A total of 51 OS events were observed (18 in the pembro arm, 33 in the placebo arm). Median OS was NR for both arms (HR 0.54, 95% CI 0.30−0.96; P=0.0164 [one-sided]); the p-value did not cross the statistical hypothesis testing boundary. The estimated OS rate at 24 mo was 96.6% with pembro vs 93.5% with placebo. 470 pts (96.3%) and 452 pts (91.1%) experienced ≥1 all-cause adverse events (AEs) with pembro vs placebo, respectively. Grade 3-5 all-cause AEs occurred in 158 pts (32.4%) with pembro and 88 pts (17.7%) with placebo. No deaths related to pembro occurred. Conclusions: Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs placebo in pts with intermediate-high, high risk or M1 NED RCC. Additional follow-up is planned for the key secondary endpoint of OS. KEYNOTE-564 is the first positive phase III study with a checkpoint inhibitor in adjuvant RCC, and these results support pembro as a potential new standard of care for pts with RCC in the adjuvant setting. Clinical trial information: NCT03142334.

350 Background: The role of cytoreductive nephrectomy (CNx) in patients with metastatic renal cell carcinoma (mRCC) is currently in question. Assessing the benefits and risks of CNx is challenging, with a lack of validated prognostic tools. Biomarkers of the systemic inflammatory response have prognostic utility in mRCC and are included in the IMDC score used to predict survival in patients with mRCC treated with systemic therapy. We sought to investigate their role in patients with mRCC who had undergone CNx. Methods: A cohort of 68 patients, suitable for first-line VEGFR inhibitor (VEGFRi) systemic therapy, who had undergone CNx for mRCC, were identified from a clinical database of patients referred to a regional mRCC service. Inflammatory biomarkers from routine blood tests (haemoglobin, white cell count, neutrophil count, platelets, C-reactive protein (CRP), albumin) and the IMDC score, measured at the time of diagnosis of mRCC, were recorded. The relationship between these and overall survival and time to VEGFRi (tVEGFRi) was examined using Kaplan-Meier and Cox-regression methods. Results: Data were available for 68 patients. Median survival was 33.7 months. On multivariate analysis, albumin ( < 35g g/dL v ≥35 g/dL) and CRP (≤ 10 mg/L v > 10 mg/L) were independently associated with overall survival (p = 0.027 and p = 0.034 respectively). Albumin stratified survival from 24.7 to 87.2 months (p < 0.0001) and CRP from 29.4 to 82.3 months (p = 0.004). 40 (59%) patients subsequently commenced VEGFRi therapy. Median tVEGFRi was 18.1 months, with only 5 (7%) patients commencing treatment within 3 months. 16 (24%) patients yet to receive systemic therapy remain alive after a median 54.0 months follow-up. On multivariate analysis, albumin was also predictive of tVEGFRi (p = 0.037), stratifying tVEGFRi from 6.07 to 45.7 months (p = 0.002). Conclusions: These results highlight that biomarkers of the systemic inflammatory response are strong prognostic factors in mRCC patients who have undergone CNx. Albumin and CRP, but not IMDC, predict survival in this patient group. Significantly, the population investigated here differ from those included in the CARMENA and SURTIME studies, with a majority undergoing surveillance prior to VEGFRi therapy. Our results support a role for CNx in patients where deferred systemic therapy strategies may be employed. Albumin may assist in clinical decision making when considering when to start systemic therapy. We advocate further studies to investigate the prognostic role of these simple, routine clinical tests in patients with mRCC undergoing CNx.

348 Background: A subset of patients with metastatic renal cell carcinoma (mRCC) follow an indolent disease course. Given the toxicity and non-curative nature associated with systemic anti-cancer therapy (SACT), some patients may benefit from initial active surveillance (AS). However, selecting patients suitable for this approach is challenging. Biomarkers of systemic inflammation predict survival in mRCC, both independently and as part of the International Metastatic Database Consortium (IMDC) risk score. We sought to use these biomarkers to characterise the time to initiation of SACT (tSACT) in mRCC patients on AS. Methods: 126 mRCC patients clinically assessed and commenced on AS prior to any systemic therapy were retrospectively identified from a regional mRCC clinical database. Patients who underwent metastasectomy for oligometastatic disease at any time were excluded. The primary endpoint, tSACT, was defined as the time from radiological diagnosis of mRCC until SACT initiation, or death, or censorship if continuing AS at follow-up date. Inflammatory biomarkers from routine blood tests (haemoglobin, white cell count, neutrophil count, platelets, C-reactive protein (CRP), albumin) and the IMDC score, measured at the time of diagnosis of mRCC, were recorded. The relationship between these and tSACT was examined using Kaplan-Meier and Cox-regression methods. Results: 66 (52%) patients had commenced SACT. 17 (13.5%) had died without commencing SACT (median survival of the 17 was 40.4 months, range 9.1-130.2 months, and comorbidities may have affected fitness for starting therapy or led to all-cause mortality). 43 patients remained on AS, with minimum and median follow-up of 12.6 months and 39.6 months respectively. The median tSACT was 17.2 months (IQR 8.8-34.8 months). On univariate analysis, CRP and albumin were predictive of time on AS ( p= 0.01 and p= 0.049 respectively). On multivariate analysis, only CRP was independently associated with tSACT ( p= 0.035), stratifying tSACT from 9.1 months (CRP > 10) to 20.9 months (CRP≤10) ( p= 0.009). 111 (88.1%) patients were IMDC 0-1, while 12 (9.5%) and 3 (2.4%) were IMDC 2 or 3 and may have had comorbidities that influenced the initial AS decision. In our cohort the IMDC risk score did not predict time on AS. Conclusions: These results highlight that some patients with mRCC may undergo active surveillance for a marked time period before SACT initiation. We identify routine biomarkers of the systemic inflammatory response that predict time to systemic therapy. In particular CRP, a simple measure of inflammation, stratifies the time to initiation of SACT across a clinically significant time period. This simple, widely available test may help to objectively inform clinical decisions about AS in patients in mRCC. Additional experience is necessary to further define the risks and benefits of this approach.

3094 Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-01 was designed to investigate the safety and tolerability of continuous, daily dosing with SRA737 and to evaluate preliminary efficacy in expansion cohorts of prospectively-selected genetically-defined subjects with advanced tumors. Methods: The escalation phase employed an accelerated titration design starting at 20 mg administered orally in 28-day cycles. Incremental 100% dose escalations in single-subject cohorts were followed by a rolling-6 design once SRA737-related ≥ Grade 2 toxicity was observed during Cycle 1. The expansion phase enrolled subjects prospectively selected by next-generation sequencing with: high grade serous ovarian, colorectal, metastatic castration-resistant prostate, non-small cell lung, and head and neck cancers. Results: In escalation, 18 subjects received SRA737 in 9 dose level cohorts, from 20 to 1300 mg QD; median treatment duration 62.5 days (range 1 to 226). Of these subjects, 3 experienced dose limiting toxicity (DLT; inability to receive 75% of the planned dose); 2 at 1300 mg QD due to gastrointestinal intolerability and 1 at 500 mg BID due to thrombocytopenia. The maximum tolerated dose (MTD) was established at 1000 mg QD or 500 mg BID. The Cmax and AUC0-24 at 1000 mg QD were 2391 ng/mL and 26795 ng∙h/mL respectively and the Cmin (411 ng/mL) exceeded that determined in preclinical models to be effective. Doses ≥ 300 mg QD also exceeded this level. Of 462 subjects prospectively screened for genetic alterations associated with Chk1 sensitivity, 93 were enrolled in expansion across all tumor types. Overall, the most commonly reported treatment-emergent adverse events were diarrhea (70%), nausea (64%), vomiting (51%), and fatigue (47%); the majority were of mild to moderate severity. Conclusions: In this first-in-human trial of SRA737 monotherapy, the MTD was 1000 mg/day and based on overall tolerability and PK, the recommended Phase 2 dose is 800 mg/day. The successful enrollment of prospectively-selected genetically-defined subjects will allow response data to be correlated with genomic profiles hypothesized to confer sensitivity to Chk1 inhibition. Clinical trial information: NCT02797964.

TPS3147 Background: Nucleoside analogs form the backbone therapy for both hematological and solid malignancies. However, their clinical effectiveness is severely limited by key cellular resistance mechanisms linked to increased breakdown, impaired activation and transport. NUC-7738 is a phosphoramidate transformation of cordycepin (3’-deoxyadenosine; 3’-dA), a derivative of adenosine that was first isolated from Cordyceps sinensis. The cytotoxic effect of 3’-dA is largely attributed to intracellular generation of the triphosphate metabolite, 3’-dATP, terminating DNA and RNA synthesis. Although 3’-dA has shown potent anti-tumor activity in non-clinical studies, it has not been successful in clinical studies mainly because of rapid enzymatic degradation by adenosine deaminase. NUC-7738 is not a substrate for adenosine deaminase and has been designed to bypass the key resistance pathways which have limited the clinical effectiveness of cordycepin. Methods: NuTide:701 is a two-part, first-in-human Phase I study in patients with advanced solid tumors and lymphoma who have exhausted all standard treatment options. The primary objective is to determine the RP2D and schedule of NUC-7738. Secondary objectives include safety, PK/PD and anti-tumor activity. Part 1, in patients with advanced solid tumors, will establish the RP2D and dose administration schedule of NUC-7738 for Part 2. Part 2 will further evaluate the selected RP2D and designated dosing schedule in an expansion cohort of patients with advanced solid tumors or lymphoma. The study initiated in Q1 2019. Clinical trial information: NCT03829254.

TPS3167 Background: CDC7 is a protein with key roles in DNA replication initiation, the intra-S-phase checkpoint and M-phase completion. CDC7 is over-expressed in malignant compared to non-malignant cells, particularly those with TP53 mutations, making it an attractive therapeutic target. LY3143921 hydrate is an orally administered ATP-competitive CDC7 inhibitor. Pre-clinical studies in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC) demonstrate favourable anti-cancer activity, particularly in squamous NSCLC and in CRC with TP53 null and missense mutations. We hypothesise that solid tumours mutated in TP53 will be sensitive to LY3143921 therapy. Methods: This is a first-in-human, phase I trial of LY3143921 hydrate (LY3143921) monotherapy given twice daily, continuously on a 21 day schedule until disease progression, patient (pt) withdrawal or unacceptable toxicity (NCT03096054). Eligible pts have histologically proven advanced/metastatic solid tumours for which no further standard therapy exists and WHO PS 0-1. Pts have regular clinical assessment and tumour imaging every 2 cycles. Phase Ia (dose escalation) is recruiting in a 3+3 design following 3 initial single patient cohorts (starting dose 30 mg OD), enriching for patients with malignancies associated with p53 mutations (CRC, sqNSCLC, high grade serous ovarian, squamous cell oesophageal, squamous cell head & neck, urothelial, pancreatic and triple negative breast cancer). Recruitment to cohort 6 (180 mg BD) is ongoing. On determination of the maximum tolerated dose (MTD) and recommended phase II dose and schedule (RP2D), 2 expansion cohorts (≤ 25 pts each) of patients with CRC and sqNSCLC will be evaluated. Primary objectives: assess safety and tolerability of LY3143921, determine MTD and RP2D. Secondary objectives: evaluate preliminary efficacy and PK profile of LY3143921. All pts will have archival tumour tissue retrospectively analysed, while patients in phase Ib will also have pre- and on-treatment tumour biopsies. Evaluation of potential predictive and pharmacodynamic biomarkers including p53 mutations, phosphorylated MCM2, cyclin B1 and molecular subgroups of target tumours will be included. Clinical trial information: NCT03096054.

e16578Background: The randomised phase III METEOR trial showed survival benefit of cabozantinib over everolimus in patients with mRCC who progressed after VEGF targeted therapy. We report real worl...

TPS3109 Background: The cell surface protein CD47 is expressed or over-expressed on many tumor types. CD47 binds to signal regulatory protein alpha (SIRPα) on macrophages resulting in a “don’t eat me” signal that blocks host cell phagocytosis of the tumor cells, thus allowing them to escape removal by the innate immune system. Recent data indicate that anti-CD47 antibodies also contribute to an effective anti-tumor T cell response in immune-competent mice. Therefore, anti-CD47 antibodies are a new class of immune checkpoint inhibitors that modulate both the innate and adaptive immune systems. Ti-061 is a novel IgG4 humanized monoclonal antibody that specifically binds to CD47 with Kd values range from 100 – 500 pM. Ti-061 exhibits cross-species binding to cynomolgus monkey, mouse and rat CD47, enabling efficacy and toxicity testing across species. Ti-061 binds to CD47 on RBCs; however, it does not cause agglutination of RBCs in vitro from any of the species tested. Ti-061 exhibits anti-tumor activity in several in vivo mouse tumor models. This ongoing Phase 1-2 study will assess the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of Ti-061 alone and in combination with other anti-cancer agents in patients with advanced malignancies. Methods: Part A is an open-label, dose-escalation study of Ti-061 administered as a weekly 1-hour IV infusion at doses ranging from 1 to 20 mg/kg. Once the MTD/RP2D or “active dose” is determined, patients with specific solid tumors and high CD47 expression will be enrolled in 4 or more expansion cohorts. Up to 160 patients with histologically confirmed solid tumors, ECOG PS 0-1, adequate blood counts (Hb≥ 10 g/dL), organ function, and archival or fresh tumor tissue will be enrolled in Part A, and will be treated until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint is safety, which will be assessed using NCI-CTCAE v4.03. Secondary endpoints include PK, PD, objective response rate (ORR) and progression-free survival (PFS), which will be assessed using RECIST v1.1. The results of this study will support further development of Ti-061 in combination with checkpoint inhibitors (Part B) and other anti-cancer agents.