ABBV-637 is an antibody-drug conjugate consisting of an epidermal growth factor receptor (EGFR)–targeting antibody and BCL-XLinhibitor. Preclinical data demonstrate potent antitumor activity of ABBV-637 plus OSI in mutant EGFR NSCLC through reactivation of the apoptotic pathway. This phase 1 dose escalation and expansion study (NCT04721015) explored the safety and preliminary efficacy of ABBV-637 as second- (2L) and third-line (3L) combination therapy with OSI. Enrolled adults had relapsed/refractory (RR) NSCLC with EGFR mutation, ECOG 0–1, and prior response and subsequent disease progression on OSI. Enrolled patients being treated at 2L and 3L had no inclusion/exclusion criteria for specific targetable mutations. ABBV-637 (12 or 20 mg/kg) was dosed IV Q4W; OSI (80 mg) was given daily in 28-day cycles. Endpoints included the rates of treatment-emergent adverse events (TEAEs), objective response (ORR), disease control (DCR), and best overall response. Disease- and drug-related biomarkers were evaluated. Forty-two patients were treated; median age was 65 (range: 44–79), and 64% had ≥2 prior lines of therapy. Median duration of ABBV-637 treatment was 113 days (range: 28–288). Most common TEAEs were increases in aspartate (38%) and alanine aminotransferase (33%), nausea (33%), and fatigue (21%). The ORR was 14% in 3L cohorts and 10% in 2L (Table). DCR was 73% and 65% in 3L and 2L, respectively. In 2L, confirmed responders did not have targetable bypass alterations.Table: 1318MOCharacteristicTotal (N=42)Safety, n (%)TEAEs41 (98)Grade ≥317 (40)ABBV-637-related deaths0 (0)Preliminary efficacy, n (%)Cohort A†+ Bi‡ (3L) (n=22)Cohort Bii§ (2L) (n=20)Best overall response*Complete response (CR)0 (0)0 (0)Partial response – all (PR)5 (23)3 (15)Partial response – confirmed (cPR)3 (14)2 (10)Stable disease (SD)11 (50)10 (50)Progressive disease6 (27)7 (35)Objective response rate (CR+cPR)3 (14)2 (10)Disease control rate (PR+SD)16 (73)13 (65)*Based on RECIST 1.1; †dose escalation (3L; n=5); ‡dose expansion (3L; n=17); §dose expansion (2L). 2L, 2nd-line therapy (post osimertinib alone); 3L, 3rd-line therapy (post osimertinib and platinum chemotherapy). Open table in a new tab *Based on RECIST 1.1; †dose escalation (3L; n=5); ‡dose expansion (3L; n=17); §dose expansion (2L). 2L, 2nd-line therapy (post osimertinib alone); 3L, 3rd-line therapy (post osimertinib and platinum chemotherapy). ABBV-637 plus OSI showed clinical activity and a manageable safety profile in patients with RR NSCLC. Biomarker data suggest that response to ABBV-637 plus OSI may be enriched by excluding patients with targetable bypass mechanisms; ongoing research is needed to confirm association of mutation and patient selection.

IOS-1002 is a recombinant homodimer of the human leukocyte antigen B57 free heavy chain linked to a human IgG4 Fc backbone associated with human β2 microglobulin. The binding of IOS-1002 to LILRB1, LILRB2, and KIR3DL1 receptors blocks the interaction with tumor-expressed ligands such as HLA-G. Through this mechanism, IOS-1002 enhances the immune response of diverse sets of both innate and adaptive immune cells and leads to tumor cell killing. The anti-tumor effect is enhanced by combining IOS-1002 with a PD-1 check point blockade inhibitor in pre-clinical models The present study evaluates the safety, tolerability, pharmacokinetics, efficacy, immunogenicity, and pharmacodynamics of IOS-1002 as monotherapy and as combination therapy with a PD-1 monoclonal antibody in subjects with advanced solid tumors. The phase 1a/1b trial is being conducted at five sites in Australia and has started enrollment as of March 2023. The trial is separated in 2 parts: Dose Escalation (A): Subjects are enrolled into 10, 30, 100, 300, 800, and 1200 mg dose levels sequentially and treated with IOS-1002 Q2W IV. Guided by the dose-limiting toxicities (DLTs) observed, an accelerated dose titration design is used for the first 3 dose levels followed by a 3+3 dose escalation. The DLT period is defined as 4 weeks following cycle 1 day 1 infusion. Once monotherapy reaches the 800 mg dose level, the combination therapy with a 3 + 3 dose escalation starts at a dose of 300 mg Q2W for IOS-1002 in combination with a PD-1 mAb at approved dose and schedule. The IOS-1002 RP2D or MAD as identified for monotherapy and PD-1 combination will then be used in the dose expansion part. Dose Expansion (B): Following the toxicity and activity profile observed in part A, a tumor-specific cohort expansion study in up to 6 potential disease entities with 20 patients per cohort will be initiated, 3 as IOS-1002 monotherapy and 3 as IOS-1002 + PD-1 combination. Depending on the disease entity and line of treatment, the PD-1 cohort will include PD-1 naïve, pre-exposed and refractory patients, respectively. Clinical Trials Registry Number: NCT05763004. ImmunOs Therapeutics AG. ImmunOs Therapeutics AG.

1562 Objectives: Glioblastoma multiforme (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years from diagnosis. EphA3 is a tumor restricted antigen expressed in 100% of the tumor vasculature as well as on some stromal cells in GBM, and other solid tumors. Ifabotuzumab is a non-fucosylated IgG1κ antibody targeting EphA3. A Phase I study of ifabotuzumab in hematological malignancies showed it to be well tolerated and clinically active. Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in patients with recurrent GBM. Methods: Eligible patients received a trace (5mg) dose of zirconium-89 labelled ifabotuzumab (89Zr-ifab) on day 1 followed by sequential PET imaging over 1 week to determine its biodistribution and quantitative tumor uptake. Safety assessments and PK sampling were also undertaken. The primary objective is to determine the safety and recommended Phase II dose of ifabotuzumab in GBM patients. Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr-ifabotuzumab, the frequency of EphA3-positive GBM, and response rates. On day 8, patients commenced weekly ifabotuzumab infusions over 2 hours in one of three cohorts planned (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg). On day 36, pts received both 89Zr-ifab and ifabotuzumab, allowing assessment of receptor occupancy. Response rate (RANO) and survival data were collected. Patients then continued on ifabotuzumab until disease progression. Results: To date, 8 of 12 planned patients have enrolled (6 at 3.5 mg/kg, 2 at 5.25 mg/kg). Mean age is 51 years (range 24-71 yrs) and 5 patients are male. Treatment emergent adverse events included infusion reactions in 3 patients, seizures in 2 patients, cerebral oedema in 2 patients, rash in 1 patient, pruritis in 1 patient, headaches in 7 patients and eye disorder in 2 patients. Most were considered related to study drug except seizure in 1 patient, headaches and eye disorder. Seizures and infusion reactions were readily managed with increased premedications after the first occurrence. The best response in cohort 1 (to date) is stable disease for 23 weeks.89Zr-ifab PET/CT scans showed rapid, specific targeting at all known tumor sites and in all patients, and no specific normal tissue uptake. No saturation of uptake of 89Zr-ifab in tumor was seen with unlabelled ifabotuzumab co-infusion. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature. The mean ± SD PK parameters for first infusion of 89Zr-ifab were T½α 10.54 ± 4.52 hr, T½β = 101.51 ± 54.08 hr, V1 = 3.89 ± 0.66 L, CL= 108.37 ± 46.43 mL/hr. Conclusions: 89Zr-ifab demonstrates sensitive, specific and reproducible targeting of the tumor microenvironment in GBM patients. The imaging changes suggest modulation of the tumor vasculature and treatment effect. Enrolment is on-going.

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.

Malignant mesothelioma (MM) is an aggressive malignancy of the pleura with limited therapeutic options, and is associated with a poor prognosis. EGFR is known to be highly over-expressed in mesothelioma with reported EGFR overexpression between 44 to 97%. We have investigated an anti-EGFR antibody (ABT-806), which is tumour specific and robustly inhibits EGFR-expressing tumors. We have previously shown that ABT-806 ADCs demonstrate potent anti-tumor activity in 806 immunohistochemistry (IHC) positive MSTO-211H MM cell line xenograft model. We present data in MM using ABT-806 novel ADCs [ABT-414 (ABT-806- monomethyl auristatin F), ABBV-221 (ABT-806- monomethyl auristatin E), ABBV-322 (ABT-806- pyrrolobenzodiazepine)] and ABBV-321 (Affinity-matured ABT-806- pyrrolobenzodiazepine) in MM patient derived xenografts (PDX). We evaluated expression of EGFR and mAb 806 IHC in MM cell lines and PDXs. PDXs were implanted into 5 to 10 NOD-Scid mice per group and treated with control ADC, saline, cisplatin or ABT-806 ADCs and followed longitudinally with caliper measurements. Comparative statistics were performed in Graphpad prism. Quantitative biodistribution and imaging of mAb806 uptake (89Zr-ch806) were performed to allow correlation of mAb806 concentration in MM tumours. Three PDX models were selected according to their 806 IHC statuses (2 epithelioid 806 IHC positive, 1 biphasic histology 806 IHC negative). In one epithelioid PDX model, ABBV-322 resulted in significantly reduced tumor growth on day 27 post therapy with median tumour volumes of 180 mm3 (ADC control) compared with 78mm3 (ABBV-322; p=0.0159 two-sided). Moreover, the median survival was also significantly longer in ABBV-322 treated models (p=0.018). In the other epithelioid PDX model, ABBV-321 also resulted in significant responses (median 428mm3 (ADC control) vs 167mm3 (ABBV-321, p= 0.0201) [Figure 1]. In the 806 IHC negative PDX model, the differences in tumor volumes between all groups were found to be non-statistically significant (ADC control vs ABT-414, ADC control vs ABBV-221, ADC-control vs ABBV-321 groups) with p=0.0597 for one-way ANOVA. MSTO211H cell line xenograft model also demonstrated significant anti-tumour response to both ABT-414 and ABBV-221 (p<0.01). Whole-body PET/MR images also confirmed localization of 89Zr-Ch806 to the established MSTO-211H xenograft tumours. In a disease with limited therapies, ABT-806 targeting ADCs in MM demonstrated significant responses in 806+ PDX and cell lines. These data support clinical expansion of these compounds in 806+ MM patients.

Background: ICOS, a member of CD28/B7 superfamily, is expressed on T cells (TC) after TC receptor engagement with cognate antigen. ICOS provides a costimulatory signal augmenting TC expansion, function and survival. GSK609 is a humanized, IgG4 antibody engineered to reduce Fc-mediated depleting effects yet retain cross-linking for potent agonist activity against human ICOS. GSK609's unique profile as a pure TC agonist void of TC depleting effects offers antitumor potential as monotherapy and in rational combinations with agents that modulate key immune pathways. Methods: INDUCE-1 evaluates safety, PK, PD, and antitumor activity of GSK609 given as an intravenous (IV) infusion every 3 weeks (Q3W) alone (Part 1) and in combination with 200 mg pembrolizumab [P] Q3W (Part 2). Modified toxicity probability interval informed dose escalation [DE] decisions (≥ 3 pts/dose level [DL]). Eligible pts must have relapsed disease, adequate organ function, no active autoimmune disease requiring treatment; prior immunotherapy was allowed. Pts remained on treatment until progression or unacceptable toxicity. Blood was collected for safety, PK, PD; tumor biopsies collected for PD. Results: To date, 79 pts enrolled, Part 1: 22 in DE and 30 in PK/PD cohort; Part 2: 27 in DE. In Part 1, 45 pts (87%) had adverse events (AEs); most frequent (≥20%) regardless of cause were fatigue (29%) and pain (19%). Fatigue was the most frequent treatment-related (TR) event (15%); liver enzyme increases in 1 pt were the only TR AEs leading to discontinuation. In Part 2, 25 pts (93%) had AEs; most frequent were nausea (33%), fatigue (26%), arthralgia (22%), decreased appetite (22%) and vomiting (22%). Pyrexia was the most frequent TR AE (7%); no TR AE led to discontinuation. No DLTs were reported in DE with Part 2 ongoing at planned, top DL. In Part 1, GSK609 showed approximate dose proportional increases in systemic exposures over the 0.01 – 3 mg/kg DLs. Clinical activity was seen in Part 1 and Part 2. Conclusions: GSK609 +/- P was well tolerated; MTD was not reached. AEs were manageable and most were unrelated to study treatment. Complete safety, PD and clinical activity data from DE and PK/PD will be presented. Clinical trial identification: NCT02723955, first posted date: March 31, 2016. Legal entity responsible for the study: GlaxoSmithKline. Funding: GlaxoSmithKline. Disclosure: A. Hansen: Research support: Genentech/Roche, Merck, GlaxoSmithKline, Bristol Myers Squibb, Novartis, Boston Biomedical, Boehringer-Ingelheim. T.M. Bauer: Consulting/advisory: Ignyta, Guardant Health, Loxo, Pfizer, Moderna Therapeutics; Research funding: Daiichi Sankyo, Medpacto, Inc, Incyte, Mirati Therapeutics, Medimmune, Abbvie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Principa Biopharma, Genentech/Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, Peleton, Immunocore, Roche, Aileron Therapeutics, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio. M. Maio: Patient's fee for subjects enrolled in clinical trials: BMS, GSK, AZ, Roche, MSD, Incyte, Novartis; Advisor/Board member: BMS, GSK, AZ, Roche, MSD, Incyte; Honorarium, compensation for Advisory Boards: BMS, GSK, AZ, Roche, MSD, Incyte; Travel expenses related to participation to Ad Boards/Scientific meetings: BMS, GSK, AZ, Roche, MSD, Incyte. H. Gan: Consulting/advisory: Abbvie, Merck Serono; Speakers' bureau: Abbvie, Bristol Myers Squibb, Ignyta; Research funding: Abbvie; Travel/accommodation expenses: Abbvie, Ignyta, MSD. D. Rischin: Research funding: Genentech/Roche, Merck, Amgen, Regeneron, Bristol-Myers Squibb, GSK. M. Millward: Consulting/advisory: Bristol-Meyers Squibb, Roche, Merck, Sharp & Dohme, Novartis, AstraZeneca. A.J. Olszanski: Consulting/advisory: Array, Bristol-Meyers Squibb, Merck, Takeda; Research funding: Amgen, Bristol-Meyers Squibb, EMD Serono, Immunocore, Incyte, Kura, Kyowa Hakko Kirin, Lilly, Pfizer, GSK, Takeda, Checkmate, Boston Biomedical, Astellas, Targovax. D.C. Cho: Honoraria: Bristol-Myers Squibb, Exelixis, Genentech; Consulting/advisory: Pfizer, Prometheus E. Paul, S. Yadavilli, J. Sadik Shaik, C. Ellis, H. Zhou: Employee and shareholder: GSK. M. Ballas: Employee and shareholder: GSK; Stockholder: BMS. E.V. Schmidt: Employment and stock holder: Merck. A. Hoos: Employee and shareholder: GSK; Non-Executive Director and stockholder: Imugene. E. Angevin: Consulting/advisory: GSK, MSD; Research funding: Abbvie, Roche, Sanofi. All other authors have declared no conflicts of interest.

BackgroundDepatuxizumab mafodotin (depatux-m, formerly ABT-414) is an EGFR-directed antibody-drug conjugate being developed for treatment of EGFR-amplified glioblastoma (GBM). As therapeutic pressure engenders tumor adaptations, it is important to understand the stability of biomarkers targeted by precision medicine approaches such as depatux-m. Therefore, we assessed EGFR amplification (amp) and expression in longitudinally-sampled GBMs from patients (pts) treated +/- depatux-m to explore biomarker stability.

Malignant mesothelioma (MM) is an aggressive malignancy of the pleura with limited therapeutic options, and is associated with a poor prognosis. EGFR is known to be highly over-expressed in mesothelioma with reported EGFR overexpression between 44 to 97%.We have developed an anti-EGFR antibody (ABT-806), which is tumour specific and robustly inhibits EGFR-expressing tumours. We aimed to establish the validity and feasibility of targeting tumour expressed EGFR in MM using ABT-806 novel ADCs (ABT-414 and ABBV-221). We evaluated EGFR and mAb 806 immunohistochemistry in 4 MM cell lines (MSTO-211H, NCI-H2052, NCI-H28, NCI-H2452) and performed in-vitro cell proliferation assays to evaluate the antineoplastic potential of mAb806-related ADCs. In-vivo therapeutic studies using the biphasic mesothelioma cell line (MSTO-211H) were conducted with treatment groups involving ABT-414, ABBV-221, ADC control, cisplatin chemotherapy. We also performed quantitative biodistribution and imaging of mAb806 ADC uptake (89Zr mAb806 ADC) to allow correlation of mAb806 ADC concentration in tumours. mAb806 to be bound strongly to three of four MM cell lines (MSTO-211H, NCI-H2052 and NCI-H28). Cell proliferation assays (CPA) also demonstrated ABT-414 and ABBV- 221 had significant cell growth inhibition demonstrated in the range between 1 to 10ug/ml for MM cell lines. In MSTO211H xenograft model significant anti-tumour response to both ABT-414 and ABBV-221 (p<0.01), was demonstrated. High, specific targeting of 89Zr-ch806 to MM tumour in-vivo was also shown. ABT-806 ADCs show potent anti-tumour activity in MM model, and warrant further exploration as a potential therapy for MM.

Background: Tislelizumab, a humanized IgG4 mAb with high affinity and specificity for PD-1, was engineered to minimize binding to FcɤR on macrophages, thus abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy. Previous reports from this first-in-human study (NCT02407990), and other early phase studies, suggest tislelizumab was generally well tolerated and had antitumor activity in pts with advanced solid tumors. Methods: Patients with UC received tislelizumab at doses of 2, 5, or 10 mg/kg Q2W or Q3W, and 200 mg Q3W. Tumor cell (TC) and immune cell (IC) PD-L1 expression were retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Adverse events (AEs) were assessed per NCI-CTCAE 4.03 and tumor assessments were performed every 9 wks using RECIST v1.1. Results: A total of 17 pts with UC (median age, 71 yr [range 39–79]) received tislelizumab, the majority of which received 5 mg/kg Q3W (n = 11). All pts were Caucasian and 14 were male; median number of prior systemic anticancer therapies was 1 (range 0–4). Treatment-related AEs (TRAEs) occurring in ≥ 3 pts included fatigue (n = 5), infusion-related reaction (n = 3), and rash (n = 3). Grade ≥3 TRAEs were fatigue, hyperglycemia, and type 1 diabetes mellitus (T1DM; n = 1 each). Three pts experienced serious TRAEs (infusion-related reaction [n = 1], hyperglycemia and T1DM [n = 1], and pneumonitis [n = 1]). As of 27 Apr 2018, median duration of follow up was 8.8 mo (range 0.9–29.1) and 2 pts remained on treatment. All pts were evaluable for response. Confirmed CR (n = 1) and PR (n = 4) were observed; SD was achieved in 3 pts. ORR and DCR were 29% (95% CI 10.3, 55.9) and 47% (95% CI 22.9, 72.1), respectively. Sixteen samples were available for PD-L1 evaluation. Responses were observed in 4 (n = 1 CR; n = 3 PR) of 10 pts with PD-L1+ tumors (defined as ≥ 25% TC or IC expressing PD-L1 by IHC), while 1 (PR) in 6 pts with PD-L1– tumors responded. Conclusions: Tislelizumab was generally well tolerated in pts with UC and responses were observed in both PD-L1+ and PD-L1– diseases. Tislelizumab is currently being investigated in China as monotherapy for pts with PD-L1+ UC (CTR20170071). Editorial acknowledgement: Editorial and medical writing assistance were provided by Regina Switzer, PhD (SuccinctChoice Medical Communications, Chicago, IL). Clinical trial identification: NCT02407990. Legal entity responsible for the study: BeiGene, Ltd. Funding: BeiGene, Ltd. Disclosure: S. Sandhu: Honoraria: Amgen, Bristol-Myers Squibb, Merck; Consulting or advisory role: Amgen; Speakers' bureau: Bristol-Myers Squibb, Merck. A. Hill: Stock and other ownership interests: Tasman Oncology; Research funding: Tasman Oncology; Travel, accommodations, expenses: Bristol-Myers Squibb. H. Gan: Consulting or advisory role: AbbVie, Merck Serono; Speakers' bureau: Abbvie, Bristol-Myers Squibb, Ignyta; Research funding: AbbVie; Travel, accommodations, expenses: AbbVie, Ignyta, Merck Sharp & Dohme. M. Friedlander: Honoraria: AstraZeneca, MSD; Consulting or advisory role: AstraZeneca, MSD; Research funding: BeiGene (Inst). M. Voskoboynik: Travel, accommodations, expenses: Bristol-Myers Squibb. P. Barlow: Travel, accommodations, expenses: MSD, Roche.J. Song, Y. Zhang, L. Liang: Employee: BeiGene. J. Desai: Consulting or advisory role: Amgen, Beigene, Bionomics, Eisai, Lilly, Novartis; Research funding: Bionomics (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Roche (Inst). All other authors have declared no conflicts of interest.

Background: Researchers are questioning the rationale for current rigidity of eligibility criteria in cancer clinical trials. In ineligible patients, the effect of RFSF on subsequent standard treatment (SST) is unclear. We review RFSF in a tertiary centre and their impact on SST. Methods: From Feb 2011-Mar 2018, patients were identified from a tertiary hospital cancer trials screening log. Data collected included RFSF, SST details, & change in RFSF. Patients were excluded if RFSF was biomarker-related, absence of measurable target lesion, inadequate tissue sample, incorrect prior treatment or stage, or patient choice. Results: 216 patients were eligible. Median age was 62 years (range 18-87), 82% had ECOG PS 0-1. 42% had ≥1 comorbidity. Most common cancers were lung (28%), melanoma, colon and pancreatic (all 11%). RFSF were rapid disease progression (PD, 16%); PS 2-4 (12%); abnormal liver function (aLFT, 12%), of which 19 had liver metastases; brain metastases (11%); active comorbidity (11%); renal injury (RI, 17, 8%); suspected metastases (15, 7%) and concurrent cancer (11, 5%). Other reasons (19%) included abnormal blood test, heart disease, contraindicated drugs and leptomeningeal disease. 132/216 (61%) had SST. 8/132 (6%) had a dose reduction of SST, most commonly due to renal impairment (n = 3) or active comorbidities (n = 2). RFSF stabilised/improved in 87/132 (66%) on SST. Of note, all those with aLFTs in the absence of liver metastases improved, however only 26% of aLFTs with documented liver metastases improved, and only 19% of poor PS patients improved. Response to SST occurred in 44/132 (33%). 31/216 (14%) died ≤2 months post screening, mostly from PD (12/35, 34%), PS (8/26, 31%) and aLFT with liver metastases (9/19, 47%). Conclusions: Most RFSF do not impact SST in cancer patients, especially abnormal organ function with no direct organ involvement. Rapid PD does not affect outcomes. Those with RFSF of poor PS and aLFTs due to liver metastases are less suitable for SST and rarely respond. Careful broadening of trial eligibility is warranted. Legal entity responsible for the study: Austin Health. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Introduction: Background: BGB-A317 is a humanized IgG4 anti-PD-1 mAb blocking PD-L1/PD-L2 binding to PD-1, thereby restoring T-cell-mediated tumor inhibition. BGB-A317 is differentiated from other checkpoint inhibitors by its engineered Fc-hinge region that precludes FcγR1 mediated binding to macrophages/myeloid-derived suppressor cells (MDSCs) - a potential mechanism by which PD1-bound T-cells may be cleared. Upregulation of PD-1 and PD-L1, and a predominance of macrophages and MDSCs have been reported in HCC supporting the rationale for evaluation of BGB-A317 in patients with HCC. At SITC 2016 we have reported the safety and efficacy data of a phase 1 study of BGB-A317 in patients with advanced solid tumors. Here we present the preliminary results in the HCC subset of patients enrolled in this ongoing phase 1 study. Methods: Method: A phase 1A/1B, open-label, multi-center, dose-escalation and expansion study (NCT02407990) was conducted to evaluate the safety, tolerability and anti-tumor activity of BGB-A317 in patients with advanced solid tumors. Patients with histologically confirmed advanced HCC were eligible and treated every three weeks (Q3W) at a dose of 5 mg/kg. Adverse events (AEs) were assessed per NCI-CTCAE v4.03 and tumor assessments were performed Q9W using RECIST v1.1. Results: Results: As of 13 Jan 2017, 11 patients (pts) with sorafenib-refractory HCC were enrolled. The most common AEs included fatigue (2 of the 11 pts), pyrexia (2/11), productive cough (2/11), upper respiratory tract infection (2/11) and decreased appetite (2/11). Two grade 3 AEs, ascites, and upper respiratory tract infection, were reported in two different pts. Treatment–related AEs were grade 1 fatigue (1/11) and rash (1/11). Three serious AEs observed in three different pts were grade 3 ascites, grade 3 upper respiratory tract infection and death with unknown cause, and none of them were considered treatment-related. As of 24 Feb 2017, the median follow-up was 4.1 months (range 0.7 – 13.6 months) and 8/11 pts remain on study. The disease control rate (DCR), defined as the proportion of pts who have achieved complete response (CR), partial response (PR) and stable disease (SD) per RECIST v1.1, is 70%. Among 10 evaluable pts, an ongoing confirmed PR was observed in one pt with 75% sum-of-the-longest-diameter (SLD) reduction; SD was observed in 6 pts, including one pt with AFP reduction from 4399 to 5.25 ng/mL and another pt with initial documentation of PR (31% SLD reduction) at the 2nd evaluation awaiting confirmation. This study will enroll about 50 pts with HCC, and data will be updated at time of presentation. Conclusion: Conclusions: BGB-A317 appears to be tolerable in pts with refractory/relapsed HCC. The preliminary safety profile and anti-tumor activity support continued exploration and development of BGB-A317 in pts with advanced HCC.

Background: INCSHR01210 is a novel PD-1 inhibitor with a safety and activity profile that may be different from that of other PD-1 inhibitors. Methods: This is an ongoing, open-label, Phase1, dose-escalation/tumor-expansion study to evaluate the safety of INCSHR01210 in patients (pts) with relapsed/refractory solid tumors (NCT02492789). In Part 1, INCSHR01210 was administered IV at 1, 3, 6, or 10 mg/kg, initially on Day 1 of a 28-day cycle (for safety, PK and PD) and then Q2W, in a standard 3 + 3 dose-escalation design. Based on Part 1 data, Part 2 consisted of different tumor expansion cohorts, in which fixed doses of INCSHR01210 (600 mg and 200 mg Q4W) were evaluated. Results: As of data cutoff (3Feb2017), 23 pts were treated in Part 1 (median age, 62 y [range, 32–73]; 74% women). Treatment-related AEs in ≥ 20% of pts (all Gr; Gr3/4) were skin capillary hemangioma (61%; 0%) and diarrhea (26%; 4%). Skin capillary hemangiomas were scattered and typically: <1 cm in diameter; on the face and upper chest; considered Gr1/2; regressed after stopping INCSHR01210. Immune-related AEs were consistent with other PD-1 inhibitors and observed in 3 (13%) pts. Treatment discontinuation due to AEs was reported in 1 pt (10 mg/kg; Gr1 skin hemangioma [resolved after stopping treatment]). The PK profile showed a dose-dependent increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. The receptor occupancy (RO) assessment at 10 mg/kg showed a target PD-1 inhibition of ∼80% for up to 28 days. Of 21 efficacy evaluable pts, 5 (24%) had PR (median DOR, 163 days [range, 36–316]) and 4 (19%) had SD. Pts with PR included 1 pt each with SCC of the parotid gland (1 mg/kg), breast cancer (1 mg/kg), RCC (6 mg/kg), bladder cancer (10 mg/kg) and ovarian cancer (10 mg/kg). Based on the safety (including tolerability of hemangioma), PK and RO data from Part 1 and from Part 2 at 600 mg Q4W flat dosing, the remainder of Part 2 patients were treated at the 200 mg Q4W flat dose; Part 2 data will be presented. Conclusions: INCSHR01210 demonstrated manageable toxicity, but with Gr1/2 hemangioma not seen with prior PD-1 inhibitors. The recommended Phase 2 dose/schedule is 200 mg Q4W. Clinical trial identification: NCT02492789 Legal entity responsible for the study: Incyte Europe Sàrl, Geneva, Switzerland Funding: Incyte Europe Sàrl, Geneva, Switzerland Disclosure: P. Grimison: Corporate-sponsored research: Tilray, Incyte, Gilead, Tigermed, Pfizer, Merck, Boston Biomedical, Medimmune, Halozyme, Specialised Therapeutics Australia. H. Kallender, K. Sun, X. Chen: Employee at Incyte Corporation. A. Behren: CSL Ltd: Stock ownership, Corporate-sponsored research. P. Fernandez-Penas: Advisory board member: Roche, Janssen, Abbvie, Lilly, Novartis Employee: The University of Sydney, Westmead Hospital Corporate-sponsored research: Incyte. K. Woods: Corporate-sponsored research: CSL Ltd. All other authors have declared no conflicts of interest.

Aim: Aberrant EGFR signaling plays a vital role in GBM oncogenesis. ABT414 comprises an EGFR targeted antibody conjugated to the toxic agent monomethylauristatin F. An open label, 3 arm, phase I study (NCT01800695) is underway to evaluate 3 different ABT414 regimens in GBM. To understand the population most suited for ABT414 therapy, assays measuring EGFR gene amplification/protein overexpression, and the presence of EGFRvIII mutation have been developed. Methods: Total EGFR and EGFRvIII expression were measured with reverse transcription polymerase chain reaction (RTPCR). EGFR gene amplification was detected with fluorescence in situ hybridization (FISH) using 2 probes: Vysis locus specific identifier EGFR probe and Vysis chromosome enumeration probe (CEP) 7 probe. FISH utilized Ratio of EGFR to CEP 7 to identify locus specific EGFR gene amplification. Total EGFR protein expression was analyzed via immunohistochemical (IHC) using Dako pharmDx™ IHC assay. Relative expression of total EGFR and presence of EGFRvIII mRNA were determined with quantitative RTPCR. Tumor tissues from 89 pts were used for these tests. Results: IHC and RTPCR confirmed expression of EGFR mRNA and protein are correlated in GBM tissue samples (Spearman correlation is -0.86, P = 0.0026). A strong association between EGFR gene amplification and mRNA overexpression was observed. EGFRvIII mRNA was detected almost exclusively in cases with EGFR amplification. Thus far, EGFR amplification has been confirmed in 23/29 pts tested. All 6/6 pts with confirmed objective radiographic responses by Response Assessment in NeuroOncology criteria displayed EGFR gene amplification, whereas only 5/6 pts had total EGFR mRNA overexpression using RTPCR. EGFRvIII expression by RTPCR was detected in 4/6 pts. Conclusions: Assays were developed to characterize EGFR gene amplification, EGFR mRNA and protein expression, EGFRvIII status, and used to characterize EGFR status of GBM samples from pts treated with ABT414 in ongoing phase I trial. When comparing EGFR status to pt outcome, EGFR amplification by FISH had strongest association with objective radiographic responses.

Background: Patients (pts) with rGBM have a poor prognosis. EGFRamp is present in ~50% of GBMs. ABT-414 is an ADC that releases a potent toxin, monomethyl auristatin F (MMAF), inside cells with EGFRamp. Here we report the safety and efficacy of ABT-414 monotherapy at the recommended phase 2 dose (RPTD) in EGFRamp, rGBM. Methods: M12-356 (NCT01800695) is an open-label, Phase 1 study with three escalation cohorts. Study design and RPTD was reported previously (ASCO Meeting 2015, SNO Meeting 2015). Sixty pts, all with EGFRamp, rGBM, were enrolled as part of the escalation (12 pts) or expansion (48 pts) cohort treated with ABT-414 monotherapy at 1.25 mg/kg. Adults with measurable (RANO), bevacizumab-naïve, rGBMs with EGFRamp confirmed centrally were eligible. Results: As of March 1, 2016, 60 pts with EGFRamp, rGBM underwent treatment. Median age was 58 years (range, 35–80). Pts underwent 1, 2 (43% each) or 3 (13%) prior therapies. The most common treatment emergent adverse events (TEAEs) (≥20% pts) included blurred vision (65%), headache, fatigue (30% each), eye pain and photophobia (28% each). Grade 3/4 TEAEs (>1 pt) were keratitis (13%), corneal epithelial microcysts (8%), blurred vision (5%), dry eye, ulcerative keratitis and reduced visual acuity (3% each). The best RANO responses of 56 pts with complete data were: 3 (5%) partial responses, 24 (43%) stable diseases and 29 (52%) progressive diseases. Median duration of overall response in 3 patients with partial responses was 4.4 months (range, 1.9–5.6). The 6-month progression-free survival (PFS6) estimate was 25.3% [95% CI=14.8, 37.2]. Conclusions: ABT-414 monotherapy displayed frequent but mostly grade 1/2 ocular toxicities. An encouraging PFS6 (25%) was observed in this rGBM population where 56% had ≥2 prior therapies. A global randomized trial of ABT-414, alone or with TMZ, vs. TMZ or lomustine, is underway in EGFRamp, rGBM (NCT02343406).