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Background Many patients do not respond or eventually relapse on treatment with programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors due to secondary or acquired resistance; therefore, there is a need to investigate novel PD-1/PD-L1 inhibitors. Methods This open-label, non-randomised study investigated the safety and anti-tumour activity of BGB-A333, a PD-L1 inhibitor, alone and in combination with tislelizumab in patients with advanced solid tumours with progression during/after standard therapy. The primary objectives were to determine the recommended Phase 2 dose (RP2D), safety and tolerability for BGB-A333 alone and in combination with tislelizumab (Phase 1a/1b) and to determine the overall response rate (ORR) with BGB-A333 plus tislelizumab (Phase 2). Results Overall, 39 patients across Phase 1a (N = 15), 1b (N = 12) and 2 (N = 12) were enroled. In Phase 1a, an RP2D of 1350 mg was determined. In Phase 1a and 1b/2, serious treatment-emergent adverse events (TEAEs) were reported in five and eight patients, respectively. Two patients experienced TEAEs that led to death. In Phase 2, the ORR was 41.7% (n = 5/12; 95% confidence interval: 15.17%, 72.33%). Conclusions TEAEs reported with BGB-A333 were consistent with other PD-L1 inhibitors. Encouraging preliminary anti-tumour activity was observed with BGB-A333 in combination with tislelizumab. Clinical trial registration NCT03379259.

In the last decade, systemic therapies such as immune checkpoint inhibitors and BRAF-MEK inhibitors have improved the prognosis of high-risk and advanced melanoma. With improved survival, melanoma survivorship is increasingly important, particularly in patients who have a good prognosis or are diagnosed at a younger age. It is increasingly recognized that cancer and its treatment is associated with increased cardiovascular morbidity and mortality. Indeed, data from observational studies and meta-analyses of randomized controls trials in melanoma show that systemic therapies may be associated with cardiac toxicities, such as myocardial infarction, heart failure, myocarditis and stroke. Our review will discuss cardiovascular disease and risk factors in the context of melanoma and outline the importance of cardiovascular risk modification in this population.

In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab.Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Recommendations for surveillance imaging for resected melanoma vary considerably. This study examined the utility of imaging in patients with a high-risk primary melanoma undergoing a protocolized imaging schedule.This retrospective study involved data collection regarding imaging, recurrence, and outcome characteristics for patients referred to the Victorian Melanoma Service from January 2016-April 2020 and managed for resected stage IIC or III melanoma. Patients with a T4b tumor who did not undergo a sentinel lymph node biopsy were included (T4bNX). Recurrences were "clinically detected" if they were primarily detected by patient symptoms or physical examination, or 'imaging-detected' if the patient was asymptomatic. Cox regression models including time-varying co-variates were used to assess the impact of imaging-detected versus clinically-detected recurrence on overall survival.Over a median follow-up time of 2.7 years, 199 patients underwent surveillance imaging (T4bNX:22, IIC:33, IIIA:22, IIIB:60, IIIC:61, IIID:1), and 44% (n = 88) experienced disease recurrence. Imaging detected over half (53%) of all recurrences. In adjusted analyses, mortality risk was reduced after an imaging-detected compared to clinically-detected recurrence at any given time from the start of surveillance (hazard ratio 0.25, 95% confidence interval 0.10-0.66, p = .005).Our study indicates that routine imaging in the early follow-up period of resected T4bNX, stage IIC and III melanoma plays an important role in the detection of asymptomatic recurrences. Imaging-detected recurrence may be associated with a survival benefit and studies with more prolonged follow-up are required to confirm these findings.

Background Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models. Methods This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects. Results Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7–38.6%). Median duration of response was 14.9 months (95% CI, 8.7–26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6–55.8%). Conclusions Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC. ClinicalTrials.gov Identifier NCT02361723.

PURPOSE Leptomeningeal disease (LMD) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma is associated with a poor prognosis and limited treatment options. Osimertinib is a potent third-generation EGFR tyrosine kinase inhibitor with confirmed CNS penetration. This study reports on outcomes of patients with EGFR-mutated non–small-cell lung cancer who developed LMD and were subsequently treated with osimertinib. METHODS We identified patients treated with osimertinib 80 mg PO daily under a compassionate access scheme across nine tertiary Australian institutes between July 2017 and July 2020. Patient demographics, tumor characteristics, and treatment history were collected. Median overall survival, median progression-free survival, disease control rates (DCR), and overall response rates (ORR) were assessed. Kaplan-Meier analysis was performed and descriptive statistics were used. RESULTS Thirty-nine patients were analyzed of which 74% were female. Exon 19 deletions (49%) and L858R point mutations (41%) were the most common EGFR mutations. Forty-nine percentage of patients were Eastern Cooperative Oncology Group 1. The median duration of osimertinib therapy was 6 months. The extracranial DCR and ORR were 60% and 54%, and the intracranial DCR and ORR were 68% and 53%, respectively. Median overall survival was 10.5 months (95% CI, 8.17 to 15.05 months). CONCLUSION There are limited treatment options for LMD in EGFR-positive lung cancer, and osimertinib at a dose of 80 mg daily is an active therapeutic option for these patients.

Background This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma. Patients and Methods This was an open-label, two-part, multicenter study involving treatment-naive patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted. Results Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group. Conclusions Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.

Purpose Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population.

Background: SHR-A1811 is an ADC comprised of a humanized anti-HER2 monoclonal antibody (trastuzumab), a cleavable linker, and a DNA topoisomerase I inhibitor payload. Here we assessed SHR-A1811 in HER2-expressing/mutated unresectable, advanced, or metastatic solid tumors. Methods: Pts were eligible if they had HER2 positive breast cancer (BC), HER2 positive gastric/GEJ carcinoma, HER2 low-expressing BC, HER2-expressing/mutated NSCLC, or other HER2-expressing/mutated solid tumors, and were refractory or intolerant to standard therapy. SHR-A1811 at doses of 1.0-8.0 mg/kg was given Q3W (IV). The primary endpoints were DLT, safety, and the RP2D. Results: From Sep 7, 2020 to Sep 28, 2022, 250 pts who had undergone a median of 3 prior treatment lines in the metastatic setting received at least one dose of SHR-A1811 in dose escalation, PK expansion, and indication expansion part. As of data cutoff on Sep 28, 2022, 1 pt experienced DLT. Treatment-related adverse events (TRAEs) were reported in 243 (97.2%) pts. Grade ≥3 TRAEs, serious TRAEs, and treatment-related deaths were reported in 131 (52.4%), 31 (12.4%), and 3 (1.2%) pts, respectively. Interstitial lung disease (AESI) was reported in 8 (3.2%) pts. Exposures of SHR-A1811, total antibody, and the payload were generally proportional to dose from 3.2 to 8.0 mg/kg. ORR was 61.6% (154/250, 95% CI 55.3-67.7) in all pts. Objective responses were observed in pts with HER2 positive BC (88/108, ORR 81.5%, 95% CI 72.9-88.3), HER2-low BC (43/77, ORR 55.8%, 95% CI 44.1-67.2), urothelial carcinoma (7/11), colorectal cancer (3/10), gastric/GEJ carcinoma (5/9), biliary tract cancer (5/8), NSCLC (1/3), endometrial cancer (1/2), and H&N cancer (1/1). Subgroup analyses of ORR are shown in Table 1. The 6-month PFS rate was 73.9% in all pts. Conclusions: SHR-A1811 was well-tolerated and showed promising antitumor activity in heavily pretreated advanced solid tumors. Table 1. Subgroup analyses of ORR No. of prior treatment lines in metastatic setting in all pts (N=250) HER2 positive BC (N=108) HER2-low BC (N=77) Other tumor types (N=65) ≤3 81.8% (45/55) 58.7% (27/46) 36.7% (18/49) >3 81.1% (43/53) 51.6% (16/31) 31.3% (5/16) Prior anti-HER2 therapies in pts with BC (N=185)* HER2 positive BC (N=108) HER2-low BC (N=77) All BC (N=185) Any 82.2% (88/107, 73.7-89.0) 68.8% (11/16, 41.3-89.0) 80.5% (99/123, 72.4-87.1) Trastuzumab 81.9% (86/105, 73.2-88.7) 75.0% (9/12, 42.8-94.5) 81.2% (95/117, 72.9-87.8) Pertuzumab 83.0% (39/47, 69.2-92.4) 100% (5/5, 47.8-100) 84.6% (44/52, 71.9-93.1) Pyrotinib 86.9% (53/61, 75.8-94.1) 71.4% (5/7, 29.0-96.3) 85.3% (58/68, 74.6-92.7) Lapatinib 80.0% (28/35, 63.1-91.6) 100% (1/1, 2.5-100) 80.6% (29/36, 64.0-91.8) T-DM1 82.4% (14/17, 56.6-96.2) 100% (3/3, 29.2-100) 85.0% (17/20, 62.1-96.8) Other HER2-ADC (except T-DM1)** 60.0% (9/15, 32.3-83.7) 50.0% (2/4, 6.8-93.2) 57.9% (11/19, 33.5-79.8) ORR in pts with tumor types other than BC (N=65) HER2 IHC3+ or IHC2+/ISH+ (N=36) HER2 IHC2+/ISH- or IHC1+ or unknown (N=29) All other tumor types (N=65) % (n/N) 38.9% (14/36) 31.0% (9/29) 35.4% (23/65) ORR was shown as % (n/N, 95% CI) or % (n/N). *ORR is calculated using the number of subjects previously treated with anti-HER2 cancer therapy in advanced/metastatic setting as denominator; 2-sided 95% CIs are estimated using Clopper-Pearson method. **Includes RC48-ADC, A166, DP303c, MRG002, ARX788, TAA013, DX126-262, PF-06804103, and BAT8001. Citation Format: Herui Yao, Min Yan, Zhongsheng Tong, Xinhong Wu, Min-Hee Ryu, Jee Hyun Kim, John Park, Yahua Zhong, Weiqing Han, Caigang Liu, Mark Voskoboynik, Qun Qin, Jian Zhang, Minal Barve, Ana Acuna-Villaorduna, Vinod Ganju, Seock-Ah Im, Changsheng Ye, Yongmei Yin, Amitesh C. Roy, Li-Yuan Bai, Yung-Chang Lin, Chia-Jui Yen, Hui Li, Ki Young Chung, Shanzhi Gu, Jun Qian, Yuee Teng, Yiding Chen, Yu Shen, Kaijing Zhao, Shangyi Rong, Xiaoyu Zhu, Erwei Song. Safety, tolerability, pharmacokinetics, and antitumor activity of SHR-A1811 in HER2-expressing/mutated advanced solid tumors: A global phase 1, multi-center, first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT175.

The yield of baseline imaging in patients presenting with higher risk primary tumours, at least American Joint Committee on Cancer 8th edition stage IIC or III melanoma, is unclear.This retrospective study included patients referred to the Victorian Melanoma Service from January 2017 to April 2020, diagnosed with at least stage IIC or stage III melanoma. Patients with a T4b tumour and no sentinel lymph node biopsy were included as 'T4bNX'.One hundred and sixty-four patients (median age 65 years) with baseline imaging (T4bNX: 19, IIC: 30, IIIA: 21, IIIB: 43, IIIC: 50, IIID: 1) were included. The majority were male (73%), and those with T4bNX melanoma tended to be older (median age 79 years). Distant metastases were detected in 21% (4/19) of T4bNX, 3% (1/30) of stage IIC, 0% (0/21) of stage IIIA, and 6% (6/94) of stages IIIB-D melanoma patients. All stage III patients with distant metastases had palpable lymphadenopathy a presentation. Two patients had brain metastases, both of whom had T4bNX melanoma and synchronous extra-cranial metastases.Compared to stage IIC, baseline imaging detects higher rates of extra-cranial distant disease in stages IIIB-D and T4bNX melanoma. Intracranial imaging has greater yield in patients with distant extra-cranial disease.

TPS296 Background: AZD5305 is a potent and selective oral PARP inhibitor (PARPi) that specifically targets and traps PARP1, in contrast to approved PARPis which target both PARP1 and PARP2. Preclinical data suggest that PARP1 inhibition confers antiproliferative effects, while PARP2 inhibition is a major driver of hematological toxicity. Thus, AZD5305 may have an improved therapeutic index with less toxicity. The Phase 3 PROpel study showed that first-line olaparib plus abiraterone (abi) significantly improved radiographic progression-free survival (rPFS) over abi alone in pts with metastatic castration-resistant prostate cancer (mCRPC) enrolled irrespective of homologous recombination repair (HRR) gene mutations (Clarke et al, NEJM Evidence 2022). There is a need for better understanding of the benefit of adding PARPi to NHA and the potential synergy between them in early treatment of mPC. The PETRANHA study (NCT05367440) is evaluating the combination of AZD5305 with physician’s choice of NHA including abi, darolutamide, and enzalutamide, in pts with mPC. Methods: This is a multi-arm, open-label, nonrandomized dose-escalation phase study. Key eligibility criteria include age ≥18 years, histologically confirmed mPC (mCRPC or metastatic castration-sensitive prostate cancer [mCSPC], suitability for NHA treatment, ECOG PS 0–1, and life expectancy ≥16 wks. HRR gene mutation status is assessed at screening by testing blood, tumor or circulating tumor (ct) DNA; however, an identified mutation is not required for study entry. Key exclusion criteria for pts with mCRPC include previous PARPi, platinum chemotherapy, or targeted radioligand therapy. For pts with mCSPC, key exclusion criteria are the same, plus previous NHA or docetaxel in the mCSPC setting. Treatment continues until disease progression, starting an alternative anticancer therapy, or unacceptable toxicity. The primary objectives are to assess the safety and tolerability of AZD5305 in combination with NHAs, in terms of adverse events (AEs), serious AEs, and dose-limiting toxicities. Key secondary objectives include characterization of pharmacokinetics, changes in tumor size and prostate-specific antigen level, and assessment of preliminary antitumor activity by objective response rate, rPFS, and time to and duration of response by RECIST v1.1 and Prostate Cancer Clinical Trials Working Group 3 criteria. Exploratory endpoints include evaluating the role of predictive biomarkers including longitudinal assessment of ct cells and ctDNA, prostate-specific membrane antigen positron emission tomography (PET) and fluorodeoxyglucose PET. Enrollment began on June 23, 2022, in Melbourne, Australia; additional sites are planned in Australia, USA, and Europe. Clinical trial information: NCT05367440 .

This phase 1/2a, open-label study (NCT02419417) evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158, a selective bromodomain and extraterminal domain (BET) inhibitor. Dose escalation was performed with 3 BMS-986158 dosing schedules: A (5 days on, 2 days off; range, 0.75–4.5 mg), B (14 days on, 7 days off; 2.0–3.0 mg), and C (7 days on, 14 days off; 2.0–4.5 mg). Eighty-three patients were enrolled and received ≥1 BMS-986158 dose. Diarrhea (43%) and thrombocytopenia (39%) were the most common treatment-related adverse events (TRAEs). A lower incidence of TRAEs was found with schedules A (72%) and C (72%) vs. B (100%). Stable disease was achieved in 12 (26.1%), 3 (37.5%), and 9 (31.0%) patients on schedules A, B, and C, respectively. Two patients on schedule A with a 4.5-mg starting dose (ovarian cancer, n = 1; nuclear protein in testis [NUT] carcinoma, n = 1) experienced a partial response. BMS-986158 demonstrated rapid-to-moderate absorption (median time to maximum observed plasma concentration, 1–4 h). As expected with an epigenetic modifier, expression changes in select BET-regulated genes occurred with BMS-986158 treatment. Schedule A dosing (5 days on, 2 days off) yielded tolerable safety, preliminary antitumor activity, and a dose-proportional PK profile.

Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recognized as a key target of checkpoint inhibition. Davoceticept (ALPN-202) is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in vitro and in in vivo tumor models, while demonstrating favorable preclinical safety. Methods: This is a first-in-human, cohort-based, open-label dose escalation and expansion study of davoceticept in adults with advanced solid tumors or lymphoma (NCT04186637). Patients with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity. Disease assessments are evaluated by RECIST v1.1 for solid tumors. A prior presentation discussed the initial first 5 cohorts of the Q1W schedule; this presentation includes the remainder of dose escalation, including the Q3W schedule. Results: As of December 2021, 57 adults with various advanced solid tumors, most commonly colorectal and pancreatic, received davoceticept monotherapy, which was well tolerated through 10 mg/kg Q3W. Davoceticept demonstrated dose-dependent PK and target saturation. Immune-related adverse events (irAEs), occurred in 20/54 (35%), mostly involving the skin, endocrine and gastrointestinal systems. All but 2 of the irAE were grade 1-2. One DLT, chronic active gastritis grade 3, was observed at 3 mg/kg Q3W. Among 47 evaluable, unconfirmed partial responses were observed in 2 (colorectal carcinoma and renal cell carcinoma). Stable disease, defined as first scan at 6 weeks, was observed in 22; 9 (41%) demonstrated tumor volume reduction, 2 (9%) demonstrated SD for > 6 months, and 1 has an ongoing SD at 8 months. At doses above 0.1 mg/kg, pharmacodynamic ex vivo analyses demonstrated agonistic engagement of CD28 on T cells, and flow cytometry demonstrated increased circulating activated (ICOS+) and proliferating (Ki-67+) T cells, increased central memory T cells, and reduced regulatory T cells, consistent with active CD28 engagement. Conclusion: First-in-human dose escalation with davoceticept was well tolerated at doses capable of engaging CD28 costimulation in vivo, with early signs of activity in a largely treatment-refractory, non-immunogenic tumor population. These findings suggest a potential additive benefit of combining CD28 agonism with checkpoint inhibition and identify biologically active dose regimens of davoceticept for subsequent single agent development, and demonstrate further rationale for combination development. Expansion cohorts, including cutaneous melanoma and PD-L1-positive cancers, are planned. Citation Format: Michael Millward, Justin C. Moser, Diwakar Davar, Mark Voskoboynik, Nehal J. Lakhani, Rachel E. Sanborn, Jaspreet Grewal, Ajita Narayan, Mario Sznol, Keren Schieber, Hany Zayed, Christine Dela Cruz, Graciela Perez, Stanford L. Peng. Monotherapy dose escalation of davoceticept (ALPN-202), a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies (NEON-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT041.

Background: The anti-TIGIT antibody vibo in combination with pembro was well tolerated across all doses in the dose-escalation phase of the ongoing phase 1 study in pts with advanced solid tumors (NCT02964013); promising antitumor activity of vibo + pembro was observed in anti-PD-1/PD-L1-naive NSCLC. We present initial results of the dose-expansion phase in pts with advanced cervical cancer naive to PD-1/PD-L1 inhibitors. Methods: Pts with histologically confirmed, locally advanced, or metastatic cervical cancer who failed prior standard-of-care chemotherapy or who experienced early progression on definitive chemoradiation and were naive to PD-1/PD-L1 inhibitors were randomly assigned 1:1 to receive 1 of 2 doses of vibo (200 or 700 mg) + pembro (200 mg) Q3W for ≤35 cycles (~2 y) or until PD, toxicity, or pt withdrawal. Primary end points were safety and tolerability. Secondary and exploratory end points included ORR, DOR, and PFS by investigator review per RECIST v1.1. Results: Median age of the 80 pts with cervical cancer was 49 y; 58% had an ECOG PS of 1; 53% received ≥2 prior lines of therapy; and 61% had PD-L1-positive tumors. 41 pts received vibo 200 mg, and 39 received vibo 700 mg. Median follow-up was 12 mo (range, 5-26). Treatment-related AEs (TRAEs) occurred in 27 pts in each treatment group (66%, vibo 200 mg; 69%, vibo 700 mg). The most frequent TRAEs (≥15%) were rash (22%), increased lipase (17%), and pruritus (17%) with vibo 200 mg + pembro and pruritus (28%), pyrexia (21%), rash (15%), and fatigue (15%) with vibo 700 mg + pembro. Grade 3 or 4 TRAEs occurred in 29% (vibo 200 mg + pembro) and 18% (vibo 700 mg + pembro). No deaths due to TRAEs were reported. Efficacy is reported in the Table. Conclusions: Vibo + pembro was safe in pts with advanced cervical cancer. Antitumor activity was comparable between the 2 doses of vibo studied and responses were observed irrespective of PD-L1 status. Based on these data, the RP2D for vibo remains 200 mg Q3W. Efficacy By Treatment Group By PD-L1 Statusa Vibo 200 mg + Pembro n = 41 Vibo 700 mg + Pembro n = 39 PD-L1-positive n = 49 PD-L1-negative n = 21 Confirmed ORR, % (95% CI) 15 (6-29) 23 (11-39) 20 (10-34) 14 (3-36) CR, n (%) 2 (5) 5 (13) 6 (12) 1 (5) PR, n (%) 4 (10) 4 (10) 4 (8) 2 (10) SD, n (%) 12 (29) 7 (18) 14 (29) 3 (14) PD, n (%) 18 (44) 19 (49) 20 (41) 12 (57) Median DOR, months (range)b Not reached (10 to 31+) Not reached (4+ to 35+) Not reached (4+ to 35+) Not reached (21 to 27+) Median PFS, months (95% CI) 2 (2-4) 2 (2-4) 4 (2-4) 2 (1-4) CR, complete response; DOR, duration of response; PD, progressive disease; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease. aPD-L1 status was unknown in 10 patients; data were pooled across treatment groups. PD-L1 positivity was defined as combined positive score (CPS) ≥1 or when CPS was missing, as tumor proportion score ≥1% or mononuclear immune cell density score ≥2. b“+” indicates no PD present at the time of the last disease assessment. Citation Format: Ronnie Shapira-Frommer, Ruth Perets, Mark Voskoboynik, Kathryn Mileham, Adnan Nagrial, Brian Stein, Vincent Chung, Martin Gutierrez, Diana Chen, Tanya Keenan, Mohini Rajasagi, Jane Healy, Sun Young Rha. Safety and efficacy of vibostolimab (vibo) plus pembrolizumab (pembro) in patients (pts) with cervical cancer naive to PD-1/PD-L1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT508.

Background: MEDI5752 is a monovalent bispecific antibody targeting PD-1 and CTLA-4. The bispecific format is engineered to preferentially inhibit these two checkpoints on activated T cells in tumors, where co-expression is particularly abundant. This may maximize tumor-specific response and reduce the peripheral toxicity that is common when targeting these checkpoints independently. Here we present dose-escalation data from a phase I, open-label, multicenter study in advanced solid tumors (NCT03530397). Methods: Eligible patients (pts) were ≥18 years old (ECOG PS 0-1) with tumors not amenable to standard therapy. Pts were treated at 10 dose levels from 2.25-2500 mg IV Q3W until progression or unacceptable toxicity. Primary objectives were safety and identification of maximum tolerated dose (MTD). Secondary objectives included preliminary antitumor activity by RECIST v1.1, PK and immunogenicity. Exploratory objectives included evaluation of pharmacodynamic (PD) biomarkers. Results: At data cutoff (Sept 30, 2021), 86 pts (median age, 60.5 years; male, 75.6%; Asian, 57.0%) were enrolled. The most common tumor types were RCC (22.1%), NSCLC (16.3%), and head and neck cancer (8.1%); 95.2% had received prior systemic therapy and 90.7% were immunotherapy-naïve. MEDI5752 showed dose-dependent PK and sustained peripheral PD-1 receptor occupancy (>90%) at doses >225 mg. Dose-dependent increases in peripheral T cell proliferation (Ki67+) and activation (ICOS+) plateaued at doses ≥500 mg and demonstrated CTLA-4 specific blockade in the range of tremelimumab 6-10 mg/kg. At doses ≥500 mg, MEDI5752 significantly expanded new and existing T-cell clones, likely broadening the tumor antigen-driven T-cell response. Across all doses, objective responses were seen in 19.8% of pts (n=17, 1 complete and 16 partial [PR]). Median duration of response was 17.5 months. Molecular response (defined as ≥50% reduction in ctDNA) occurred in 36.5%. Doses ≥1500 mg (n=53) were poorly tolerated with Grade (G) 3/4 treatment-related AEs (TRAEs) in 50.9%; discontinuations due to TRAEs in 45.3%, and death in 1 (at 2000 mg). However, doses Conclusions: MEDI5752 showed encouraging antitumor activity with durable clinical benefit. Doses Citation Format: Ben Tran, Mark Voskoboynik, Sang-We Kim, Charlotte Lemech, Enric Carcereny, Sun Young Rha, Myung-Ju Ahn, Enriqueta Felip, Ki H. Lee, Eduardo C. Alvarez, James Chih-Hsin Yang, Paolo A. Ascierto, Mariano P. Pulla, Dan Freeman, Xuyang Song, Shelby D. Gainer, Patrick Mitchell, Ikbel Achour, Deepa S. Subramaniam, Seock-Ah Im. MEDI5752, a novel PD-1/CTLA-4 bispecific checkpoint inhibitor for advanced solid tumors: First-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT016.

2505 Background: Immunoglobulin-like transcript 3 (ILT3) is an inhibitory receptor associated with immune tolerance and T-cell suppression within the tumor microenvironment. MK-0482, a novel humanized IgG4 mAb targeting ILT3, is undergoing phase 1 evaluation ± pembrolizumab (pembro) in advanced solid tumors (NCT03918278; MK-0482-001). Dose escalation data are presented. Methods: Eligible patients with advanced solid tumors were enrolled into sequentially escalating dose cohorts of MK-0482 monotherapy (0.2-2250 mg) or MK-0482 (7.5-2250 mg) + pembro 200 mg; both were administered IV Q3W for up to 35 cycles or until progressive disease (PD), unacceptable toxicity, death, or withdrawal. Patients receiving MK-0482 monotherapy could cross over to MK-0482 + pembro after PD. Primary objectives were safety, tolerability, and determination of the recommended phase 2 dose (RP2D). Secondary and exploratory objectives included assessing pharmacokinetics (PK), blood receptor occupancy (RO), anti–drug antibodies (ADA), and objective response rate (ORR) per RECIST v1.1 by investigator assessment. Results: Seventy-five patients were enrolled (n = 29, MK-0482 monotherapy; n = 46, MK-0482 + pembro); 8 patients crossed over to receive the combination. Median age was 63 years (range, 34-86); 73% had ECOG PS 1, 72% received ≥2 lines of prior anticancer therapy, and 32% received prior PD-1/PD-L1 inhibitors. Treatment-related AEs (TRAEs; any-grade/grade 3 or 4) were reported in 34%/7% of patients with MK-0482 monotherapy, 67%/4% with MK-0482 + pembro, and 50%/13% in those who crossed over. The most common TRAEs (≥10% of all patients) were pyrexia (10%) with MK-0482 monotherapy; fatigue (24%) and arthralgia, diarrhea, hyperthyroidism, hypothyroidism, and pruritus (11% each) with MK-0482 + pembro; and arthralgia (25%), hyperthyroidism and hypothyroidism (13% each) for patients who crossed over. Dose-limiting toxicities occurred in 2 patients who received MK-0482 + pembro: 1 grade 5 myositis (MK-0482 750 mg; the only TRAE leading to death) and 1 grade 2 myositis (MK-0482 2250 mg). Preliminary PK and blood RO data suggested that target-mediated drug disposition of MK-0482 was likely saturated in blood mononuclear cells at doses ≥75 mg. ADA to MK-0482 was observed in ̃20% of patients, but no clear impact on MK-0482 PK was observed. A confirmed ORR of 15% (8 PR) was observed in patients who received MK-0482 + pembro, including patients who crossed over; no confirmed responses were observed in patients who received MK-0482 monotherapy. MK-0482 750 mg + pembro was selected as the RP2D based on the totality of data. Conclusions: MK-0482 ± pembro was generally well tolerated, and combination therapy provided modest antitumor activity in patients with heavily pretreated advanced solid tumors. The RP2D of MK-0482 + pembro is under further evaluation in tumor-specific cohorts. Clinical trial information: NCT03918278.

2560 Background: Strong preclinical rationale supports combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly of CD28, a critical T cell costimulatory molecule recognized as a key target of checkpoint inhibition. Davoceticept (ALPN-202) is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in multiple tumor models in vitro and in vivo, while demonstrating favorable preclinical safety. Methods: This is an open-label dose escalation and expansion study of davoceticept in adults with advanced solid tumors or lymphoma (NCT04186637). Patients with cancers refractory to standard therapies including CPIs, or cancers without available standard or curative therapy are eligible. Dose escalation studied two dose schedules, Q1W and Q3W. Objectives include safety and tolerability, PK, PD and preliminary anticancer activity. Disease assessments are evaluated by RECIST v1.1 for solid tumors. A prior presentation discussed the first 5 cohorts of the Q1W schedule; this presentation updates progress in dose escalation, including the Q3W schedule. Results: As of January 2022, 57 adults with various advanced solid tumors, most commonly colorectal and pancreatic, received davoceticept monotherapy, which was well tolerated through 10 mg/kg Q3W. It demonstrated dose-dependent PK and target saturation. Immune-related AEs (irAEs), occurred in 20/57 (35%), mostly of the skin, endocrine and gastrointestinal systems. All but 4 of the irAE were grade 1-2. Only one DLT (chronic active gastritis grade 3) was observed at 3 mg/kg Q3W. Among 48 evaluable patients, unconfirmed partial responses were observed in 2 (colorectal and renal cell). Stable disease, at first scan at 6 weeks, was observed in 23 (48%); 11 (23%) demonstrated volume reduction (target lesion ΔSLD < 0%); 2 had SD for > 6 months, and 1 had an ongoing SD at 8 months. At doses above 0.1 mg/kg, ex vivo analyses showed agonism of T cell CD28, and flow cytometry demonstrated increased circulating activated (ICOS+), proliferating (Ki-67+) and central memory T cells, and reduced regulatory T cells, consistent with CD28 engagement. Conclusions: Davoceticept was well tolerated at doses capable of engaging CD28 costimulation in vivo, with early signs of activity and peripheral immune activation in a largely treatment-refractory, non-immunogenic tumor population. These findings support an additive benefit of combining CD28 agonism with checkpoint inhibition and identify biologically active dose regimens of davoceticept for subsequent single agent development, and provide further rationale for combination study. Expansion cohorts, including cutaneous melanoma and PD-L1-positive cancers, are planned, and a combination study with pembrolizumab has initiated (NCT04920383). Clinical trial information: NCT04186637.

Background Ligation of glucocorticoid-induced tumor necrosis factor receptor (GITR) decreases regulatory T cell-mediated suppression and enhances T-cell proliferation, effector function, and survival. MK-1248 is a humanized immunoglobulin G4 anti-GITR monoclonal antibody agonist. Methods In patients with advanced solid tumors, MK-1248 (starting dose, 0.12 mg) was tested alone and with pembrolizumab (200 mg) according to a 3 + 3 dose escalation design (ClinicalTrials.gov identifier NCT02553499); both treatments were administered intravenously every 3 weeks for ≤4 and ≤35 cycles, respectively. The safety and tolerability, maximum tolerated dose, and pharmacokinetics/pharmacodynamics were explored. Results Twenty patients received MK-1248 monotherapy; 17 received combination therapy. The most frequent tumor types were colorectal cancer (n = 8), melanoma (n = 6), and renal cell carcinoma (n = 4). MK-1248 was generally well tolerated at the maximum tested doses of 170 (monotherapy) and 60 mg (combination). No dose-limiting toxicities (DLTs) or treatment-related deaths occurred. Adverse events (AEs) occurred in 36 of the 37 patients (97%); the most common were vomiting (n = 13 [35%]), anemia (n = 10 [27%]), and decreased appetite (n = 10 [27%]). Grade 3 to 5 AEs occurred in 19 of the 37 patients (51%). Treatment-related AEs occurred in 18 of the 37 patients (49%): 9 of the 20 patients (45%) on monotherapy and 9 of the 17 patients (53%) on combination therapy. Among the 17 patients receiving combination therapy, 1 achieved a complete response and 2 achieved a partial response, for an objective response rate of 18%; no patients achieved an objective response with monotherapy. The disease control rate (stable disease or better) was 15% with monotherapy and 41% with combination therapy. Conclusions MK-1248 was generally well tolerated at doses up to 170 (monotherapy) and 60 mg (combination), with no DLTs or treatment-related deaths. Combination therapy provided limited antitumor responses.

Background The impact of radiotherapy (RT) on the efficacy and toxicity of immune checkpoint inhibitors (ICIs) in patients with metastatic non–small-cell lung cancer (NSCLC) is unclear. Materials and Methods We identified patients with metastatic NSCLC treated with the anti-programmed death 1 antibodies nivolumab or pembrolizumab between January 2016 and May 2019 at 3 tertiary centers, who were also treated with palliative RT either during or within 3 months of starting anti-programmed death 1 treatment. Patient demographics, tumor characteristics, and treatment history were collected. Response rates, progression-free survival (PFS), and overall survival (OS) were analyzed and correlated with RT use. Results A total of 269 patients were identified, with a median follow-up of 19.4 months. The median age was 70 years (range, 35-90 years), and they were 63% male, 60% smokers, and 65% had adenocarcinoma histology. At the commencement of ICI treatment, the majority (86%) had ≥ 1 line of prior therapy and 34% had brain metastases. A total of 102 (38%) patients received RT within 3 months of starting ICI or subsequently during ICI treatment. Of patients that received RT, 86 (84%) received conventional hypofractionated RT, and, in the majority, 81 (79%) the intent of RT was symptom control. The use of RT did not increase grade 3/4 immune-related adverse events. The overall median PFS was 2.0 months (95% confidence interval, 1.3-2.6 months) and the median OS was 9.0 months (95% confidence interval, 6.4-9.5 months). There were no significant differences in median PFS (3.0 vs. 2.0 months; P = .515) and median OS (9.0 vs. 9.0 months; P = .917) in the patients who received RT versus those that did not. Conclusions In patients with metastatic NSCLC, the addition of RT to ICI was not associated with increased toxicity or improved survival.

434 Background: Combination of anti-VEGF compounds and immune checkpoint inhibitors is an approved therapy across multiple solid tumors, including advanced HCC. This phase Ib study (NCT03468426) is assessing BI 836880 (bispecific VEGF/Ang2 nanobody) + ezabenlimab (anti-PD-1 antibody) in pts with advanced solid tumors. The recommended phase 2 dose (RP2D) of BI 836880 720 mg + ezabenlimab 240 mg given IV every 3 weeks was determined in Part 1. In Part 2, RP2D was assessed in 7 expansion cohorts. We report data from cohorts in HCC after prior sorafenib/lenvatinib (cohort F) and untreated unresectable HCC (cohort G). Methods: Pts with locally advanced or metastatic HCC, Child-Pugh class A, not eligible for surgical or locoregional therapies were enrolled. Cohort F enrolled pts who had progressed on or after first-line treatment with sorafenib or lenvatinib or who had discontinued due to poor tolerability after ≥2 weeks of treatment. Cohort G enrolled pts who had received no prior systemic therapy for HCC. Treatment continued until disease progression, undue toxicity or consent withdrawal. Primary endpoint is objective response rate (ORR) by RECIST 1.1. Results: As of Aug 2021, 30/31 pts have been treated in cohorts F/G: 87/77% male; median age 65/64 yrs. Follow-up is ongoing in both cohorts. 9/19 pts in cohorts F/G remain on treatment; median (range) duration of treatment is 175 (42–532)/ 169 (42–336) days in cohorts F/G. All pts were evaluable for response in cohort F: confirmed ORR to date is 40% (1 complete response; 11 partial responses [PRs]). Of 28 evaluable pts in cohort G, confirmed ORR to date is 21% (6 PRs). 12 (40%) pts in cohort F and 18 (64%) in cohort G have stable disease. In cohort F, AEs were reported in 28 (93%) pts, most frequently hypertension and proteinuria (each 30%). In cohort G, AEs occurred in 26 (84%) pts, most frequently ascites (26%) and thrombocytopenia (19%). 24 (80%) pts in cohort F and 15 (48%) in cohort G had treatment-related AEs (TRAEs). Most frequent TRAEs were proteinuria (27%), infusion-related reactions (IRRs) and hypertension (each 20%) in cohort F, and hypertension (13%), IRRs, hypothyroidism and diarrhea (each 10%) in cohort G. There were 3 pts with G5 AEs in cohort F (COVID-19 pneumonia [n = 1]; low Glasgow coma score and dyspnea [n = 1]; hepatic cirrhosis [n = 1]) and 1 G5 AE in cohort G (hepatic failure); none were considered related to treatment. AEs leading to discontinuation occurred in 2 pts in cohort F (G3 hepatic encephalopathy and G2 duodenal ulcer) and 3 in cohort G (G5 hepatic failure [n = 1]; G2 acute kidney injury and G1 decreased appetite [n = 1]; G2 diarrhea [n = 1]). Conclusions: BI 836880 + ezabenlimab had a manageable safety profile and showed promising activity in pts with untreated and second-line post-sorafenib/lenvatinib advanced HCC. Data continue to mature, particularly in cohort G. Cohort F has been expanded by a further 30 pts. Clinical trial information: NCT03468426.

Background: Combining anti-VEGF/Ang2 and anti-PD-1 therapy promotes an immunopermissive state, supportive of T-cell-mediated tumour cell destruction. This phase Ib study is assessing BI 836880 plus ezabenlimab in patients (pts) with advanced solid tumours. In Part 1 (dose escalation in pts with advanced NSCLC), the recommended phase 2 dose (RP2D) was determined as BI 836880 720 mg + ezabenlimab 240 mg IV q3w. Here, we report updated results, including data from Part 2 (expansion cohorts). Methods: Part 2 has 7 cohorts: metastatic (m) NSCLC after checkpoint inhibitor (CPI) monotherapy (Cohort A);mNSCLC after chemotherapy (CT) + CPI (Cohort B);mSCLC after CT ± CPI (Cohort C);recurrent GBM (1st and 2nd recurrence;Cohort D);immunotherapy-resistant m-melanoma (Cohort E);HCC after prior sorafenib or lenvatinib (Cohort F);and previously untreated unresectable HCC (Cohort G). Primary endpoint is objective response rate (complete response [CR] + partial response [PR]). Results: As of March 2021, 215 pts have been treated (Part 1: 14, Part 2: 201 [Cohort A, 35;B, 32;C, 19;D, 31;E, 32;F, 29;G, 23];70% male, median age 62 yrs). Any and ≥G3 AEs (any-cause) were reported in 183 (85%) and 72 (33%) pts. 118 (55%) pts had drug-related AEs, most commonly asthenia (13%) and hypertension (12%). 7 pts had G4 AEs (non-related hyperkalaemia + cardiac arrest, laryngospasm, gastrointestinal perforation;drug-related anaphylactic reaction, cholestatic hepatitis, acute pancreatitis, increased transaminases);9 pts had G5 AEs (non-related COVID-19 pneumonia, epilepsy, intracranial haemorrhage, cardio-respiratory arrest, haemoptysis, hepatic failure, general physical health deterioration, Glasgow coma scale abnormal + shortness of breath;drug-related tracheal haemorrhage). 35 (16%) pts had immune-related AEs and 15 (7%) had AEs leading to discontinuation. 179 pts were evaluable for response: 1 had confirmed CR (Cohort F), 22 had PR (Part 1: 2;Part 2: 20 [Cohort A, 4;C, 5;D, 4;E, 3;F, 3;G, 1]) and 110 had stable disease. 106 pts remain on treatment. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile, with preliminary activity in a range of tumour types. Clinical trial identification: NCT03468426. Editorial acknowledgement: Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Hannah Simmons MSc, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim. Legal entity responsible for the study: Boehringer Ingelheim. Funding: Boehringer Ingelheim. Disclosure: N. Girard: Financial Interests, Personal, Advisory Role: Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, BMS, MSD, Takeda, GSK, AbbVie, Pharmamar, Janssen, Sanofi;Financial Interests, Personal, Funding, Travel/accommodation/expenses: Roche, AstraZeneca, BMS MSD Oncology;Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Boehringer Ingelheim. M. Wermke: Financial Interests, Personal, Advisory Role: MSD, Novartis, Kite, Heidelberg Pharma, Roche, Boehringer Ingelheim;Financial Interests, Personal, Other, Honoraria: BMS, Merck, Roche, Novartis, Kite, Boehringer Ingelheim, AstraZeneca;Financial Interests, Personal, Funding, Travel/Accommodation/Expenses: Glenmark, BMS, AstraZeneca. E. Ledin: Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim. D. Kim: Financial Interests, Personal, Advisory Role: Health Insurance Review & Assessment Service, Korea;Financial Interests, Personal, Invited Speaker: Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology, Taiwan Lung Cancer Society;Financial Interests, Institutional, Principal Investigator, Clinical Trial Funding: Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer-Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiich-Sankyo, GSK, Hanmi, Janssen, Merus, MIrati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeuti;Non-Financial Interests, Person l, Advisory Role: Amgen, AstraZeneca, BMS / ONO Pharmaceuticals, Daiich-Sankyo, GSK, Janssen, Pfizer, SK Biopharm, Takeda, Yuhan;Non-Financial Interests, Personal, Member of the Board of Directors: Asian Thoracic Oncology Research Group, Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology;Other, Personal, Funding, Travel support for advisory board meeting attendance: Amgen, Daiichi-Sankyo. J. Bennouna: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, MSD, AstraZeneca, Roche, Servier, Bayer, AMGEN;Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, MSD, AstraZeneca, Roche;Financial Interests, Institutional, Research Grant: AstraZeneca. T. Lesimple: Financial Interests, Personal, Advisory Role: MSD, Novartis, BMS, Pierre Fabre;Financial Interests, Personal, Speaker’s Bureau: MSD, Novartis;Financial Interests, Institutional, Research Grant: Roche. E. Felip: Financial Interests, Personal, Advisory Board: Amgen;Financial Interests, Personal, Advisory Board: AstraZeneca;Financial Interests, Personal, Advisory Board: BAYER;Financial Interests, Personal, Advisory Board: Beigene;Financial Interests, Personal, Advisory Board: Boehringer-Ingelheim;Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb;Financial Interests, Personal, Advisory Board: Eli Lilly;Financial Interests, Personal, Advisory Board: F. Hoffman-La Roche;Financial Interests, Personal, Advisory Board: Glaxo Smith Kline;Financial Interests, Personal, Advisory Board: Janssen;Financial Interests, Personal, Advisory Board: Medical Trends;Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme;Financial Interests, Personal, Advisory Board: Merck Serono;Financial Interests, Personal, Advisory Board: Peptomyc;Financial Interests, Personal, Advisory Board: Pfizer;Financial Interests, Personal, Advisory Board: Puma;Financial Interests, Personal, Advisory Board: Regeneron;Financial Interests, Personal, Advisory Board: Sanofi;Financial Interests, Personal, Advisory Board: Syneos Health;Financial Interests, Personal, Advisory Board: Takeda;Financial Interests, Personal, Speaker’s Bureau: Amgen;Financial Interests, Personal, Speaker’s Bureau: AstraZeneca;Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb;Financial Interests, Personal, Speaker’s Bureau: Eli Lilly;Financial Interests, Personal, Speaker’s Bureau: F. Hoffmann-La Roche;Financial Interests, Personal, Speaker’s Bureau: Janssen;Financial Interests, Personal, Speaker’s Bureau: Medscape;Financial Interests, Personal, Speaker’s Bureau: Merck Sharp & Dohme;Financial Interests, Personal, Speaker’s Bureau: Merck Serono;Financial Interests, Personal, Speaker’s Bureau: Peervoice;Financial Interests, Personal, Speaker’s Bureau: Pfizer;Financial Interests, Personal, Speaker’s Bureau: Springer;Financial Interests, Personal, Speaker’s Bureau: Touch Medical;Financial Interests, Personal, Member, Independent Member of the Board: Grifols. D. Berz: Financial Interests, Personal, Other, Honoraria: Oncocyte;Other, Personal, Other, Honoraria: Sun Pharma;Other, Personal, Other, Honoraria: Caris;Other, Personal, Other, Honoraria: Takeda;Other, Personal, Other, Honoraria: Natera;Other, Personal, Other, Honoraria: Jazz Pharma;Other, Personal, Other, Honoraria: Genentech;Financial Interests, Personal, Advisory Role: Oncocyte;Other, Personal, Advisory Role: Sun Pharma;Other, Personal, Advisory Role: Biocept;Other, Personal, Advisory Role: Prelude;Financial Interests, Personal, Speaker’s Bureau: Oncocyte;Other, Personal, Speaker’s Bureau: Caris;Other, Personal, Speaker’s Bureau: Sun Pharma;Other, Personal, Speaker’s Bureau: AstraZeneca;Other, Personal, Speaker’s Bureau: Takeda;Other, Personal, Speaker’s Bureau: Merck;Other, Personal, Speaker’s Bureau: Natera;Other, Personal, Speaker’s Bureau: Jazz Pharma. C. Mascaux: Financial Interests, Personal, Advisory Role: Roche;Financial Interests, Personal, Advisory Role: Astr Zeneca;Financial Interests, Personal, Advisory Role: Kephren;Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb;Financial Interests, Personal, Advisory Role: MSD;Financial Interests, Personal, Advisory Role: Pfizer;Financial Interests, Personal, Other, Honoraria: Roche;Financial Interests, Personal, Other, Honoraria: AstraZeneca;Financial Interests, Personal, Other, Honoraria: Kephren;Financial Interests, Personal, Other, Honoraria: Bristol-Myers Squibb;Financial Interests, Personal, Other, Honoraria: MSD;Financial Interests, Personal, Other, Honoraria: Pfizer;Financial Interests, Personal, Other, travel, accommodations, expenses: Roche;Financial Interests, Personal, Other, travel, accommodations, expenses: AstraZeneca;Financial Interests, Personal, Other, travel, accommodations, expenses: Boehringer Ingelheim;Financial Interests, Personal, Other, travel, accommodations, expenses: Takeda. M. Voskoboynik: Financial Interests, Personal, Advisory Role: AstraZeneca. H.T. Landsteiner: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. V. Chen: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. G. Jayadeva: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. J. Alt: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Boehringer Ingelheim, BMS, Pfizer, Roche, Takeda;Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, BMS, Roche;Financial Interests, Personal, Funding, Travel/accommodation/expenses: AstraZeneca, Boehringer Ingelheim, BMS. B. Hackanson: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, MSD, AstraZeneca, BMS. All other authors have declared no conflicts of interest.

Purpose: To determine the maximum tolerated dose (MTD) of stereotactic ablative radiation therapy (SABR) in combination with immunotherapy for the treatment of patients with metastatic melanoma. The study also investigates the effects of timing and dosing of SABR on clinical efficacy. Methods: Metastatic melanoma patients with at least 2 metastases received SABR to a single metastatic site. All patients had standard dose immunotherapy with anti-PD1 or anti-CTLA4 at the discretion of their treating clinician. Following a standard 3 + 3 design, patients were escalated through 3 SABR doses (10 Gy, 15 Gy, and 20 Gy) delivered at 3 different time points (with cycle 1, 2, or 3 of immunotherapy). Dose-limiting toxicities (DLT) were defined as grade 3 or higher toxicity within 3 months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or Cox regressions were used to assess the impact of SABR dose and timing on the progression free (PFS) and overall survival (OS) of this cohort. Results: Twenty-four patients were enrolled with a median clinical follow-up of 28 months. Four patients (16.7%) developed DLTs; 1 DLT occurred at a SABR-treated site, and all patients received 15 Gy. On this basis the IDSMC recommended stopping the trial and the MTD was defined at 10 Gy. The 2-year PFS was 21.9% (95% CI, 7.1%-41.8%) and 2-year OS was 49.6% (95% CI, 28.7%-67.6%). The median PFS for those receiving 10 Gy was numerically higher than for those receiving 15 Gy, 8.3 months versus 2.1 months (P =.38). The only treatment-related factor associated with both improved PFS (HR 0.08, P

Purpose Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population. Methods Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks. Results Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3–28.9). Conclusion Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT02492789.

BACKGROUND: Checkpoint inhibitors (CPI) targeting the PD-1 and CTLA-4 pathways have demonstrated significant clinical benefit in multiple tumors, but the majority of patients exhibit or develop resistance, at least in part due to insufficient activation and/or excessive exhaustion of tumor-specific T cells. Strong preclinical rationale exists to combine CPIs with T cell costimulatory agonists, but such approaches have not yet translated into significantly improved clinical benefit. The majority of these approaches, though, have not targeted CD28, a critical T cell costimulator recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. As monotherapy, ALPN-202 has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating a favorable safety profile in preclinical toxicology studies. METHODS: This is a cohort-based, open-label dose escalation and expansion study in adults with advanced solid tumors or lymphoma (NCT04186637). The objectives of this study are to evaluate the safety, efficacy, pharmacokinetics, anti-drug antibodies, and pharmacodynamics of ALPN-202. Subjects who are refractory or resistant to standard therapy (including approved CPIs), or without available standard or curative therapy are eligible. ALPN-202 is administered by IV infusion. After two single-subject cohorts (0.001 mg/kg, 0.01 mg/kg), a standard 3+3 dose escalation (0.1-20 mg/kg) has been implemented with two dose schedules in parallel, Q1W and Q3W. Thereafter, expansion cohorts are planned to enroll subjects at a selected dose regimen(s) in selected indications. Biomarkers include tumor measurements of PD-L1, CD28, CD80 and CD86 to explore the possible relationship between baseline expression and outcomes. Other pharmacodynamic analyses include target saturation, inflammatory cytokines and immunophenotyping of circulating leukocytes. As of January 2021, the trial is continuing as planned; no DLTs have been observed through the 0.3 mg/kg cohorts (dose level 4). Citation Format: Mark Voskoboynik, Justin C. Moser, Nehal Lakhani, Michael Millward, Diwakar Davar, Wael A. Harb, Jing Yang, Gary Means, Kristi Manjarrez, Almudena Tercero, Hany Zayed, Jan Hillson, Christine Dela Cruz, Graciela Perez, Stanford L. Peng. NEON-1: a first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT213.

2547 Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating favorable safety in preclinical toxicology studies. Methods: This is a cohort-based, open-label dose escalation and expansion study of ALPN-202 in adults with advanced solid tumors or lymphoma (NCT04186637). Subjects with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two planned single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity of ALPN-202. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma. Results: As of January 2021, 20 subjects with advanced malignancies have received ALPN-202. Dose-dependent PK and target saturation have been preliminarily observed. So far, ALPN-202 has been well tolerated at dose levels ranging from 0.001 to 1 mg/kg weekly, with no DLTs. Low-grade skin toxicities (grade 1-2 rash) have been observed in 4 subjects (20%). Among 11 evaluable subjects, an unconfirmed partial response has been observed in one subject with colorectal carcinoma, while stable disease has been observed in 5 subjects with colorectal carcinoma, mesothelioma (2), cholangiocarcinoma, and renal cell carcinoma -- for a preliminary clinical benefit (PR+SD) rate of 100% (4/4) at dose levels of 0.3 mg/kg and higher, or 54% (5/11) overall (table). The meeting presentation will update this data, which is expected to include the conclusion of Q1W dose escalation, as well as immune correlates. Conclusions: First-in-human dose escalation with ALPN-202 has been well tolerated at doses capable of engaging CD28 costimulation in vivo in association with dual PD-L1/CTLA-4 checkpoint inhibition, with early signs of anti-tumor activity. These findings suggest that CD28 agonism can be safely achieved in humans, and further suggest that dose expansion with ALPN-202 is warranted to assess the relevance of controlled CD28 costimulation as a novel approach to cancer immunotherapy. Clinical trial information: NCT04186637. [Table: see text]

2579 Background: In preclinical studies, the combination of anti-VEGF/Ang2 and anti-PD-1 therapy has been shown to promote an immunopermissive state, which is supportive of T-cell-mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2, and ezabenlimab (BI 754091) is an anti-PD-1 antibody. Phase I studies investigating each as monotherapies have reported safety and preliminary antitumor activity. This ongoing Phase Ib study is evaluating the combination of BI 836880 and ezabenlimab in pts with advanced solid tumors. In Part 1 (dose escalation), the combination was feasible in pts with advanced NSCLC, with a recommended Phase II dose (RP2D) of BI 836880 720 mg + ezabenlimab 240 mg IV q3w. Here, we report updated results from Part 2 (expansion phase), which is assessing the antitumor activity and safety of the RP2D. Methods: Seven cohorts are currently recruiting pts in Part 2: metastatic (m) NSCLC after checkpoint inhibitor (CPI) monotherapy (Cohort A); mNSCLC after chemotherapy (CT) + CPI (Cohort B); mSCLC after CT ± CPI (Cohort C); 1st and 2nd recurrences of glioblastoma (GBM; Cohort D); immunotherapy-resistant m-melanoma (Cohort E); hepatocellular carcinoma (HCC) after prior sorafenib or lenvatinib ± CPI (Cohort F); and previously untreated/unresectable HCC (Cohort G). Primary endpoint is objective response rate (complete response + partial response [PR]). Results: As of January 2021, 196 pts have received BI 836880 plus ezabenlimab (14 in Part 1, 182 in Part 2 [Cohort A, 26; B, 30; C, 19; D, 31; E, 32; F, 28; G, 16]). 134 (68%) pts were male, median age was 63 years and 102 (52%) had prior CPI use. Any grade and ≥G3 adverse events (AEs; any cause) were reported by 160 (82%) and 62 (32%) pts, most commonly (all%/≥G3%) hypertension (20/8), asthenia (20/3), diarrhea, decreased appetite, and nausea (all 11/1). 95 (48%) pts had a drug-related AE, most commonly hypertension and asthenia (both 11%). 6 pts had a G4 AE (non-related: hyperkalemia + cardiac arrest, laryngospasm, gastrointestinal perforation; drug-related: anaphylactic reaction, acute pancreatitis, transaminases increased); 8 pts had a G5 AE (non-related: general physical health deterioration, epilepsy, hemoptysis, cardio-respiratory arrest, hepatic failure, intracranial hemorrhage, COVID-19 pneumonia; drug-related tracheal hemorrhage). 30 (15%) pts had immune-related AEs (3% ≥G3), including hypothyroidism (3%). 11 (6%) pts had an AE leading to discontinuation. Overall, 145 pts were evaluable for response: 9 pts achieved confirmed PR (2 pts in Part 1 and 7 in Part 2 [NSCLC, n = 3; SCLC, n = 1; GBM, n = 1; melanoma, n = 1; and 2nd-line HCC, n = 1]), 87 pts had stable disease and 49 pts had progressive disease. 111 pts remain on treatment. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile. The combination showed preliminary antitumor activity in a range of tumor types. Clinical trial information: NCT03468426.

Background: BMS-986158 is a potent, selective, and orally bioavailable small-molecule inhibitor of the bromodomain and extraterminal (BET) family of transcription modulators being evaluated in patients with various tumors in a phase 1 clinical study (NCT02419417). An integrated PK/PD analysis leveraging PK, biomarker, and safety data from the phase 1 study was performed to support dose and schedule (Sch) selection further clinical studies with BMS-986158. Methods: Five doses (0.75-4.5 mg) and 3 dosing regimens (Sch A: 5 days on, 2 days off over 21 days; Sch B: 14 days on, 7 days off; Sch C: 7 days on, 14 days off) were evaluated. Reversible thrombocytopenia (TTP) was the primary safety signal observed, and peripheral gene expression modulation was a PD biomarker indicative of drug target engagement. BMS-986158 serum PK was characterized with a 2-compartment population PK (PPK) model. A semimechanistic PK/PD model describing the platelet-reducing effect with BMS-986158 was developed to characterize platelet profiles for individual patients and to simulate and project the incidence of TTP at different doses and dosing regimens. The association of BMS-986158 exposure with expression modulation of select peripheral BET target genes, including HEXM1 and CCR2, was also examined. Results: BMS-986158 exhibited linear PK with rapid oral absorption (Tmax ≈ 2-4 h) and a terminal half-life of ≈ 60 h over the dose range of 0.75-4.5 mg. PPK modeling and simulation suggested that at the same dose level, Sch A led to comparable Cmax, with a higher Ctrough and Cavg at steady state compared with Sch B and C across the dosing interval. The semimechanistic PK/PD model predicted a higher incidence rate of TTP with Sch A than Sch C at the same dose level, and the predictions agreed with observed primary safety data from the phase 1 study. The model predicted grade 4 TTP incidence rates of 24% (95% CI, 21%-26%) and 43% (95% CI, 38%-45%) at 4.5 and 6 mg, respectively, with Sch A. This suggests that 4.5 mg would be the maximum tolerated dose, given that a 6 mg dose was predicted to exceed the target dose-limiting toxicity (DLT) rate of grade 4 TTP at 27%. The exploratory analysis of BMS-986158 exposure and expression of selected peripheral genes associated with the BET pathway suggested a direct association between BMS-986158 exposure and the magnitude of peripheral gene expression modulation. Conclusions: An integrated PK/PD analysis of BMS-986158 incorporating incidence of reversible TTP and modulation of peripheral BET target genes identified a maximum dose of 4.5 mg at Sch A for further clinical development. With the assumption that sustained gene expression modulation is desirable for BMS-986158 efficacy, Sch A, which provides sustained drug exposure, is recommended to enable continuous BET target gene expression modulation. Citation Format: Xi (Cindy) Chen, Lora Hamuro, Shodeinde Coker, John Hilton, Jennifer R. Diamond, Capucine Baldini, Mark Voskoboynik, Mihaela Cristea, William Edenfield, Kezi Unsal-Kacmaz, Donald Jackson, Abraham Apfel, Ke Xu, Li Zhu, Amit Roy, Akintunde Bello, Ronald Fleming, Paul Statkevich. Integrated pharmacokinetic (PK)/pharmacodynamic (PD) modeling leveraging PK, biomarker, and safety data to support dose and schedule selection for the BET inhibitor BMS-986158 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3021.

Background: Programmed cell death protein-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), play critical roles in the immune modulation of tumor progression. Although both pathways have overlapping elements, each has a distinct mechanism of action. Nonclinical studies have demonstrated that potential synergistic antitumor effects can result from blocking both PD-1 and PD-L1. BGB-A333 is an investigational humanized IgG1 monoclonal antibody against PD-L1 that has antitumor activity in xenograft models. Tislelizumab, a clinical-stage anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, has demonstrated clinical activity in patients with advanced solid tumors. Here we report preliminary results from the phase 1 component of an open-label phase 1/2 study (NCT03379259) of BGB-A333 alone and in combination with tislelizumab in patients with advanced solid tumors. Methods: Phase 1 of this study consisted of two parts. In Part A, patients received single-agent BGB-A333 IV Q3W at increasing doses; in Part B patients received BGB-A333 1350 mg IV Q3W + tislelizumab 200 mg IV Q3W. Eligible patients had unresectable advanced or metastatic cancer and an ECOG performance status of ≤1. Safety/tolerability profile (primary endpoint) was examined by monitoring adverse events (AEs); secondary endpoints included antitumor activity, assessed by RECIST v1.1, and the pharmacokinetic (PK) parameters of each antibody. Results: As of Oct 30, 2019, 15 patients were enrolled in Part A (450 mg, n=3; 900 mg, n=3; 1350 mg, n=6; 1800 mg, n=3) and 12 in Part B. Across both parts, patients were female (n=17/29; 63%); squamous cell carcinoma of either skin or head and neck (n=5) and ovarian cancer (n=4) were the most common tumor types. Thirteen patients (48%) had ≥2 lines of prior systemic therapy. The most common treatment-related AEs (TRAEs) were fatigue (N=5; Part A, n=3; Part B, n=2) and nausea (N=4; n=2 in A and B); the only grade ≥3 TRAE occurring in ≥1 patient was grade 3 maculo-papular rash (N=2; n=1 in A and B). One patient in Part B experienced a fatal AE (acute kidney injury) considered possibly related to study treatment. Of the 15 patients receiving BGB-A333 monotherapy in Part A, three (20%) achieved a confirmed complete response and two (13.3%) achieved a partial response (PR). Two of the 12 (16.7%) patients receiving combination therapy in Part B achieved a PR. The PK of BGB-A333 was comparable to a typical IgG1 antibody, and was similar as a single-agent or in combination with tislelizumab. The PK of tislelizumab was comparable with historical data. Conclusions: BGB-A333, alone or in combination with tislelizumab, was generally well tolerated and demonstrated antitumor activity in patients with advanced solid tumors. Based on these data, expansion cohorts have been initiated. Citation Format: Jayesh Desai, Mark Voskoboynik, Ben Markman, Sophia Frentzas, Paul Foster, Nageshwar Budha, Jing Song, Tarek Meniawy. Preliminary safety and efficacy data of BGB-A333, an anti-PD-L1 monoclonal antibody, alone and in combination with tislelizumab in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT253.

e15125 Background: APL-501 is a humanized monoclonal antibody targeting programmed cell death-1 (PD-1). APL-501 is being evaluated in patients (pts) with advanced recurrent and relapsed solid tumors who had not been previously treated with an immune checkpoint inhibitor in an ongoing 3-part Phase 1 trial (NCT03053466). Herein, we present the emerging pharmacokinetic (PK) and receptor occupancy (RO), safety and preliminary efficacy. Methods: Weight-based dose escalation (1, 3, and 10 mg/kg, Part 1) and Extension (Part 2) has been completed and the study is currently enrolling specific tumor types (MSI-H/dMMR and Carcinoma of Unknown Primary [CUP]) into the Expansion Cohorts (Part 3). Relapsed/refractory solid tumor pts were enrolled in Part 1 and Part 2. Key exclusion criteria included prior therapy targeting PD-1/PD-L1 and uncontrolled CNS metastases. APL-501 was administered IV over 1 hour every 14 days. Serum and PBMCs were collected for PK and RO analysis, respectively. RO was assessed using different T-cell markers measured by flow cytometry of PBMC. Anti-tumor activity was assessed by investigators using RECIST and irRECIST. Safety was assessed using CTCAE, v4.03. Results: As of 31 Dec 2019, 22 pts were enrolled with a mean age of 62.1 (SD: 12.2) years. ECOG PS 0/1 reported at 10/12 pts, respectively. Pts had a median number of 3 prior lines of therapy (range, 1 – 9) and median time to treatment from initial diagnosis was 30.1 months (range, 6.7 – 184.8). Across doses evaluated, APL-501 demonstrated dose proportional PK. One hundred percent (100%) RO was observed across all doses evaluated. No dose limiting toxicities were reported. Fifteen pts (68.2%) had related AEs; two pts (9.1%) had Grade ≥ 3 related AEs to APL-501. Eight pts had stable disease and two pts had partial response by RECIST (esophageal adenocarcinoma and CUP). Seven pts remained on therapy for ≥ 24 weeks. The recommended phase 2 dose (RP2D) has been determined to be 400 mg IV every 14 days (non-weight-based) based on safety and PK modeling. Conclusions: Preliminary results indicate clinical activity of APL-501 in relapsed/refractory malignant disease with a generally tolerable safety profile. The PK and RO profile, across all doses evaluated, appears comparable to marketed PD-1 inhibitors. Continued exploration of APL-501 with the RP2D in CUP and MSI-H/dMMR tumors is being planned. Clinical trial information: NCT03053466 .

Background The increasing frequency and complexity of cancer genomic profiling represents a challenge for the oncology community. Results from next-generation sequencing–based clinical tests require expert review to determine their clinical relevance and to ensure patients are stratified appropriately to established therapies or clinical trials. Methods The Sarah Cannon Research Institute UK/UCL Genomics Review Board (GRB) was established in 2014 and represents a multidisciplinary team with expertise in molecular oncology, clinical trials, clinical cancer genetics and molecular pathology. Prospective data from this board were collated. Results To date, 895 patients have been reviewed by the GRB, of whom 180 (20%) were referred for clinical trial screening and 62 (7%) received trial therapy. For a further 106, a clinical trial recommendation was given. Conclusions Numerous challenges are faced in implementing a GRB, including the identification of potential germline variants, the interpretation of variants of uncertain significance and consideration of the technical limitations of pathology material when interpreting results. These challenges are likely to be encountered with increasing frequency in routine practice. This GRB experience provides a model for the multidisciplinary review of molecular profiling data and for the linking of molecular analysis to clinical trial networks.

Background Sitravatinib is an investigational, orally bioavailable, receptor tyrosine-kinase inhibitor with immune modulatory and potential antitumor activity. Tislelizumab is an investigational, humanized IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death receptor-1 (PD-1). We assessed the safety and antitumor activity of sitravatinib plus tislelizumab in patients with advanced solid tumors. Methods This is an open-label, multicenter, non-randomized, phase Ib study (NCT03666143). This cohort evaluated anti-PD-(L)1 antibody-naive patients with recurrent, platinum-resistant, epithelial ovarian cancer who were treated with 120 mg of sitravatinib once daily in combination with 200 mg tislelizumab every 3 weeks until disease progression, unacceptable toxicity, death, withdrawal of consent, or study termination. The primary objective was to assess the safety and tolerability of this combination therapy. Overall response rate, duration of response (DOR), disease control rate, and progression-free survival (PFS) were assessed as secondary endpoints. Results As of 17 July 2019, 20 patients (median age, 66.0 years) were enrolled; median number of prior regimens was 5 (range, 2–12). All 20 patients received study drugs and were included in the safety analysis. Common (frequency ≥10%) grade ≥3 treatment-emergent adverse events (TEAEs) assessed as related to sitravatinib by investigators were hypertension (25%) and fatigue (10%). Six patients had AEs that led to sitravatinib discontinuation. The common (frequency ≥10%) grade ≥3 TEAE assessed as related to tislelizumab by investigators was increased transaminases (10%). Three patients had AEs that led to tislelizumab discontinuation. Of 17 efficacy-evaluable patients, 4 achieved confirmed partial response, 11 had stable disease, and 2 had progressive disease per RECIST version 1.1. Median PFS was 18.0 weeks; median DOR was not reached (NR) (both ranges, 12.29 weeks–NR). Conclusion Combination treatment with sitravatinib and tislelizumab was manageable and showed promising antitumor activity in patients with ovarian cancer. Clinical trial identification NCT03666143. Editorial acknowledgement Writing assistance was provided by Ira Mills, PhD, of Ashfield Healthcare Communications. Legal entity responsible for the study BeiGene. Funding BeiGene. Disclosure B. Gao: Advisory / Consultancy: Merck Sharp & Dohme. J. Goh: Advisory / Consultancy: Bristol-Myers Squibb, AstraZeneca, and Ipsen; Honoraria (self), Payment for speaking engagements: Merck Sharp & Dohme. B. Markman: Advisory / Consultancy: Novartis. M. Voskoboynik: Honoraria (self): AstraZeneca and MSD Oncology; Travel / Accommodation / Expenses: Bristol-Myers Squibb. H.K. Gan: Advisory / Consultancy: AbbVie, Bristol-Myers Squibb, and Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Eisai and Merck Serono; Research grant / Funding (self): AbbVie. J. Coward: Advisory / Consultancy: Takeda and Merck Sharp & Dohme; Research grant / Funding (self): AstraZeneca. C. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: BeiGene. X. Xiang: Shareholder / Stockholder / Stock options, Full / Part-time employment: BeiGene. J. Qiu: Shareholder / Stockholder / Stock options, Full / Part-time employment: BeiGene. Y. Xu: Shareholder / Stockholder / Stock options, Full / Part-time employment: BeiGene. L. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: BeiGene. M. Millward: Advisory / Consultancy: Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, and AstraZeneca. All other authors have declared no conflicts of interest.

BRAF mutations at codons L597 and K601 occur uncommonly in melanoma. Clinical and pathological associations of these mutations were investigated in a cohort of 1119 patients with known BRAF mutation status. A BRAF mutation was identified in 435 patients; Mutations at L597 and the K601E mutation were seen in 3.4 and 3.2% of these, respectively. K601E melanomas tended to occur in male patients, a median age of 58 yr, were generally found on the trunk (64%) and uncommonly associated with chronically sun-damaged (CSD) skin. BRAF L597 melanomas occurred in older patients (median 66 yr), but were associated with CSD skin (extremities or head and neck location - 73.3%, P = 0.001). Twenty-three percent of patients with V600E- and 43% of patients with K601E-mutant melanomas presented with nodal disease at diagnosis compared to just 14% of patients with BRAF wild-type tumors (P = 0.001 and 0.006, respectively). Overall, these mutations represent a significant minority of BRAF mutations, but have distinct clinicopathological phenotypes and clinical behaviors.

Background Optimal therapy for men relapsing after initial chemotherapy for germ cell tumours (GCT) is poorly defined. Both conventional dose salvage regimens and high-dose chemotherapy with autologous stem cell transplantation (HDCT-ASCT) have been utilised. Aims To examine patients who received HDCT-ASCT for relapsed GCT within a single Australian centre. Methods Records between 2000 and 2012 were analysed for baseline characteristics, treatment-related toxicity and survival. Prognosis at the time of HDCT-ASCT was classified according to the International Prognostic Factors Study Group (IPFSG). Results Seventeen patients received HDCT-ASCT, median age 34 (21–46), with 41% having primary refractory disease and 53% with high/very high risk disease by IPFSG. The most common regimen utilised was paclitaxel/ifosfamide followed by high-dose carboplatin/etoposide (TI-CE; n = 12). The median duration of grade 4 (G4) neutropenia was 11 days (range 9–17) with febrile neutropenia in 90% resulting in four intensive care unit admissions (8%). Median duration of G4 thrombocytopenia was 10 days (range 8–19) requiring a median of two pooled platelets bags (range 0–33) per episode. Transplant-related mortality occurred in one patient (veno-occlusive disease). Twenty-seven per cent of HDCT-ASCT cycles were associated with grade 3 mucositis (median total parenteral nutrition days = 5 (0–23)). Two-year progression-free survival (PFS) and overall survival (OS) rates were 59% and 71%. Patients who received HDCT-ASCT as second or subsequent relapse fared worse than those treated with HDCT-ASCT at first relapse (hazard ratio 0.23 (95% confidence interval: 0.04, 1.37; P-value 0.09). Three-year OS for those who received TI-CE at first relapse was 90%. Conclusions HDCT-ASCT for relapsed GCT is effective with acceptable toxicity. There was encouraging PFS/OS, particularly in a poor-prognosis cohort.

Background Pamiparib is an investigational PARP1/2 inhibitor that has demonstrated brain penetration and PARP–DNA complex trapping in preclinical studies. In the phase 1 dose-escalation/expansion study of pts with advanced solid tumors, pamiparib was generally well tolerated and showed preliminary antitumor activity. Here we report updated antitumor activity focused on the ovarian cancer cohort and safety data. Methods This is a two-stage dose-escalation/expansion study (NCT02361723). The dose-escalation study component established the pamiparib PK profile, and the recommended phase 2 dose (RP2D) of pamiparib administered orally 60 mg BID in pts with solid tumors. The dose-expansion component was conducted in pts with ovarian, breast, prostate, gastric, and small cell lung cancer. Results As of 1 January 2019, 97 pts (median age, 60 years; Eastern Cooperative Oncology Group performance status of 0, 1, or 2 [37%, 62%, and 1%, respectively]) were enrolled in the dose-escalation (n = 60) and dose-expansion (n = 37) components. Among the 97 enrolled pts, 48 pts (n = 30, ovarian pts) received 60 mg BID, the RP2D. Of 57 ovarian pts in the efficacy evaluable population (≥1 postbaseline tumor assessment), 22 (39%) achieved a confirmed objective response (complete response, n = 4; partial response, n = 18) per RECIST v1.1 criteria. Median duration of response was 12.3 months (range, 1.3–40.8). Biomarker data will be included in future analyses. In the safety population (n = 97), drug-related adverse events (AEs) in ≥ 10% of pts were nausea, fatigue, anemia, diarrhea, vomiting, and decreased appetite. The most common drug-related G3 (no G4 or G5) AEs were anemia (18.6%) and neutropenia (6.2%). AEs led to treatment discontinuation in 6.2% of pts. Four pts died due to disease progression with non-drug–related AEs. Pamiparib plasma exposure generally increased with increased dose, with a median t1/2 of ∼13 hours. Conclusions Pamiparib continues to be generally well tolerated and demonstrates antitumor activity in this update of an ongoing, phase 1 dose-escalation/expansion study in pts with advanced solid tumors. Clinical trial identification NCT02361723. Editorial acknowledgement Editorial/writing support was provided by Ira Mills, PhD, and Shannon Davis at Ashfield Healthcare Communications, Middletown, CT. Legal entity responsible for the study BeiGene. Funding BeiGene. Disclosure M. Voskoboynik: Honoraria (self): AstraZeneca; Honoraria (self): MSD Oncology; Travel / Accommodation / Expenses: Bristol-Myers Squibb. L. Mileshkin: Travel / Accommodation / Expenses, Beigene paid for flights and accommodation for me to attend and present at the ASCO STIC meeting Jan 2018: Beigene. M. Millward: Research grant / Funding (self), Per patient payments for clinical trials: Beigene; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Bristol-Myers Squibb; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Merck Sharp & Dohme; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Roche; Advisory / Consultancy, Advisory Board for Immuno-Oncology: AstraZeneca. K. Zhang: Full / Part-time employment: Beigene. M. Zhang: Full / Part-time employment: Beigene. S. Mu: Full / Part-time employment: Beigene. All other authors have declared no conflicts of interest.