Safety, tolerability and preliminary efficacy of CAN04, a first in class monoclonal antibody against IL1RAP, in combination with nab-paclitaxel and gemcitabine (NG) in subjects with pancreatic cancer.

e16228 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed on cancer and stromal cells in many solid tumors. CAN04 is a fully humanized IgG1 targeting IL1RAP blocking IL-1α and β signaling and triggering ADCC. As monotherapy, CAN04 has been administered without reaching MTD up to 15mg/kg. We report initial data from CAN04 in combination with NG in pts with pancreatic cancer (PDAC). Methods: Primary objective was to determine safety and tolerability of CAN04 in combination with standard NG as first line treatment in pts with locally advanced/metastatic PDAC. Secondary objectives included establishing preliminary efficacy. Tumor responses were evaluated according to RECIST/iRECIST. Results: 36 patients (pts) received at least 1 dose of CAN04: median age 62 yrs (46-87), 47% women, 94% stage IV, 8% had received prior adjuvant therapy; 59% ECOG 0, 41% ECOG 1. Dosing was initiated at 5mg/kg, escalated to 7.5mg/kg (n = 8) which was considered above MTD due to hematological toxicity, followed by expansion at 5mg/kg. Infusion related reactions (IRRs) were seen primarily with CAN04 priming dose of 0.5 mg/kg (25% G1, 25% G2, 3% G3). G3 or higher AEs (all/related) were dominated by hematological toxicity and reported in 89%/72% of pts (see table). SAEs were reported in 67% pts (44% G3/G4), in 33% considered related (19% G3/G4). 33% of pts discontinued due to AEs: 4 deterioration of general condition, 2 IRR, 2 bilirubin elevation, 1 bile duct obstruction, 1 hemolytic uremic syndrome, 1 pancreatitis, 1 asthenia, 1 decreased appetite, 1 pneumonitis. There were 3 on treatment deaths: disease progression, gastrointestinal obstruction and cholangitis. For the mITT efficacy analysis (n = 31), 5 pts were excluded: 3 discontinued before receiving NG (2 consent withdrawals after IRRs, tumor related physical deterioration) and 2 did not complete Cycle 1 due to cholangitis and GI obstruction respectively. 12 pts (39%) had confirmed or unconfirmed PR as best response, 8 (26%) more showed SD and 9 (29%) had PD. Six pts underwent PD confirmation: 3 pts had prolonged immune unconfirmed PD (iUPD) by iRECIST and > 50% decreases in CA19-9 and were on treatment for 4.5 (ongoing), 6 and 8 months, respectively. Clinical benefit rate (PR+SD+prolonged iUPD): 74%. At the time of this analysis, 12 pts (38%) are ongoing. Median duration of response is currently 7.5 months (1.8-13.8 months). Conclusions: The clinical benefit rate of CAN04 in combination with NG is encouraging (74%). The G3/G4 neutropenia and febrile neutropenia rate is higher than expected for NG alone. Expansion cohorts at lower CAN04 doses have been initiated. Clinical trial information: NCT03267316. [Table: see text]

Phase II trial assessing niraparib with or without dostarlimab (anti-PD-1) in recurrent endometrial carcinoma.

5574 Background: Treatment options in recurrent endometrial carcinoma (EC) are limited. Endometrioid EC shows alterations in PTEN, a possible biomarker of response to PARP inhibitors (PARPi). Similarly, homologous recombination deficiency (HRd), a biomarker of response to PARPi in ovarian cancer, is associated with serous EC harbouring TP53 mutations. Preclinical EC models have shown synergy between combining a PARPi and immune checkpoint inhibitor (ICI). Methods: A pilot multi-centre, non-randomized, phase II trial enrolled patients (pts) with recurrent serous or endometrioid EC in two consecutive cohorts (NCT03016338). In the first cohort (C1) pts received niraparib 200 or 300 mg qd, based on baseline body weight and platelet count, in 4 week (w) cycles. In the second cohort (C2) niraparib was given with dostarlimab 500 mg q 3 w for 4 cycles, followed by 1000 mg q 6 w thereafter. There was no limit on prior lines of therapy. Prior ICI was not allowed in C2. Primary endpoint was clinical benefit rate (CBR; complete, partial response or stable disease ≥16w). Secondary endpoints included toxicity assessment and ORR. CT scans were performed q 8 w. Potential biomarkers were assessed in archival tissue by IHC (PTEN, p53, MMR, PDL-1 [threshold 1%]) and a NGS panel (including TP53, PTEN, POLE and other HRd genes). Tumour mutational burden-high (TMBh) was defined as top 20% mutation load. Results: In C1, 25 pts were enrolled (23 evaluable for response). Median age was 69 years old, 64% had serous EC, 72% were platinum resistant (PlatR) and median prior therapies was 2 (range 1-4). Median number of cycles was 3. The CBR was 20% (95% CI: 9-39) and median clinical benefit (CB) duration was 5.3 (1.8-7.2) months. The ORR was 1/23 (4%; 0-20). Related grade (g) ≥3 AEs ≥10% were anemia (24%), fatigue (16%) and thrombocytopenia (16%). In C2, 22 pts were enrolled (all evaluable) and two continue on-treatment. Median age was 64 years old, 46% had serous EC, 68% were PlatR and median prior therapies was 2 (1-6). Three pts had MMR deficient (MMRd) tumors (14%) and one pt a POLE mutation (5%). Median number of cycles was 3. The CBR was 31.8% (16-53) and median CB duration was 6.8 months (3.7-9.5). The ORR was 3/22 (14%; 3-35), out of the three responders one had MMRd and one a POLE mutation. Related g≥3 AEs ≥10% were anemia (27%) and neutropenia (14%). No significant correlation was detected between CB and IHC markers (PTEN, p53, MMR, PDL-1), or NGS ( PTEN, TP53, HRd TMBh) in C1 and C2. Conclusions: Niraparib as single agent for treatment in a PlatR enriched recurrent EC population showed modest activity with clinical benefit rate at 16w of 20%. The combination of niraparib and dostarlimab showed a clinical benefit rate at 16w of 31.8% in a predominantly PlatR recurrent EC. PTEN loss by IHC or NGS, and alterations in HRd genes did not correlate with clinical benefit. Clinical trial information: NCT03016338.

Real-world data of fulvestrant as first-line treatment of postmenopausal women with estrogen receptor-positive metastatic breast cancer

Goals of endocrine therapy for advanced breast cancer (ABC) include prolonging survival rates, maintaining the quality of life, and delaying the initiation of chemotherapy. We evaluated the effectiveness of fulvestrant as first-line in patients with estrogen receptor (ER)-positive ABC with relapse during or after adjuvant anti-estrogenic therapy in real-world settings. Retrospective, observational study involving 171 postmenopausal women with ER-positive ABC who received fulvestrant as first-line between January 2011 and May 2018 in Spanish hospitals. With a median follow-up of 31.4 months, the progression-free survival (PFS) with fulvestrant was 14.6 months. No differences were seen in the visceral metastatic (14.3 months) versus non-visceral (14.6 months) metastatic subgroup for PFS. Overall response rate and clinical benefit rate were 35.2% and 82.8%. Overall survival was 43.1 months. The duration of the clinical benefit was 19.2 months. Patients with ECOG performance status 0 at the start of treatment showed a significant greater clinical benefit rate and overall survival than with ECOG 1–2. Results in real-world settings are in concordance with randomized clinical trials. Fulvestrant continues to demonstrate clinical benefits in real-world settings and appears be well tolerated as first-line for the treatment of postmenopausal women with ER-positive ABC.

Phase II trial of guadecitabine priming and pembrolizumab in platinum resistant recurrent ovarian cancer.

6025 Background: Platinum resistant ovarian cancer (PROC) remains a disease of high need. Immune checkpoint inhibitors (ICI) have modest activity. We hypothesized that priming with a hypomethylating agent (HMA) guadecitabine (G) will improve the anti-tumor activity of ICI in PROC by enhancing tumor cell recognition by CD8+ T cells. Methods: This open-label phase II study used a Simon’s two-stage design. Eligible patients (pts) had recurrent PROC; ECOG PS of 0-1; normal end organ function; and measurable disease. Up to 5 prior cytotoxic regimens were allowed. Treatment consisted of G 30mg/m2 sq D1-4 and pembrolizumab (P) 200mg iv D5. Each cycle was 21 days. The primary endpoint was response rate (RR). Secondary endpoints were progression-free survival (PFS), clinical benefit rate (CBR), and toxicity assessment. Translational endpoints were LINE1 methylation in PBMCs, global tumor methylation, and immune endpoints. Tumor biopsies were obtained at baseline and after 2 cycles. If 2 patients experienced clinical benefit in stage I [n = 16], enrollment proceeded to stage II. The null hypothesis was rejected for ≥ 6 responses in 35 evaluable patients. Results: 48 pts were enrolled, 43 were treated, and 33 were evaluable for response. Histology was serous (35), endometrioid (2), clear cell (3) and other (3). Median age was 63 (range 40-88) and median number of prior regimens was 4 [range 1-8]. Two PRs were recorded in the first stage, allowing second stage of enrollment. Overall, there were 2 PRs (RR = 6.6%) and 16 pts had stable disease (SD) [48%]. The clinical benefit rate (PR + SD > 3 months) was 27%. One patient continued treatment for > 2 yrs. Grade 3-4 related toxicities were neutropenia [20], lymphopenia, (9), anemia (2), neutropenic fever (1), rash (1), and others (8). There were 13 grade 3-4 SAEs and 4 grade 5 SAEs, assessed as being unrelated to treatment. LINE1 was hypomethylated in PBMCs D5 vs. D1 (n = 21, p = 0.001). Epic arrays measured global tumor methylation, with 39579 CpG sites (0.05%) being differentially methylated (C2D5 vs. C1D1, n = 11, paired t-test; p < 0.01). Main pathways affected included endosomal transport, K+ transport, cathecolamine secretion, etc. PDL1 staining in archival tissue showed tumor staining > 0 in 16 of 35 and tumor/stroma interface staining > 0 in 20 of 35 specimens. Antigen-specific cytotoxic T cell activity was increased in CD8+ cells from ascites (C2D5 vs. C1D1). Conclusions: G+P has modest anti-tumor activity in patients with PROC, but some patients experienced prolonged disease stabilization. Biomarkers of response are being investigated. Clinical trial information: NCT02901899.

Results from the safety lead-in for a phase II study of pembrolizumab in combination with binimetinib and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC).

4031 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition and VEGF inhibition have immunomodulatory effects (upregulation of tumor major histocompatibility complex-I expression, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors) supporting clinical evaluation of combined MEKi (B), anti–PD-1 (P), and anti-VEGF (BV) in pts with mCRC. We hypothesize that the combination of binimetinib, pembrolizumab, and bevacizumab (BPBV) will result in greater clinical benefit than pembrolizumab alone. Methods: Patients with chemotherapy-refractory mCRC were evaluated (20 planned in the safety lead-in and 50 planned for total accrual). B was dosed at 45mg PO BID, P was administered at 200mg IV Q21 days, and BV was administered at 7.5mg/kg IV Q21 days. Primary objectives were safety, tolerability, and investigator-assessed ORR by RECIST 1.1. Clinical benefit rate (CR+PR+SD) and progression-free survival were secondary endpoints. Descriptive statistics were used to summarize safety and clinical activity. Results: As of January 9, 2020, 21 pts (10 KRAS/NRASmt, 11 RASwt, 21 MSS) were enrolled into the safety lead-in and were evaluable. The median number of prior therapies was 6. The BPBV combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 38%, respectively. The most frequent related Gr 3-4 AEs were aceniform rash, diarrhea, and hypertension (19%, 14%, 14% respectively). No treatment-related Gr 5 AEs occurred. A total of 17 patients were evaluable for response. Confirmed PR was observed in 2 pts (12%). SD was noted in 14 patients (82%) leading to a clinical benefit rate of 94%. 1 patient had PD as the best response to treatment. Median PFS was 6.4 months (95% CI 4.2-8.9). Molecular determinants, immune biomarkers, and updated tumor assessments of response will be presented. Conclusions: B + P + BV demonstrated a tolerable safety profile and improvements in ORR and clinical benefit rate compared to those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts were durable, suggesting benefit of this novel combination in a patient population refractory to immune therapies. Clinical trial information: NCT03475004 .

Lower-dosing ponatinib in pre-treated GIST: Results of the POETIG phase II trial.

11536 Background: Despite long-lasting responses to imatinib most metastatic gastrointestinal stromal tumors (GIST) eventually progress and subsequent treatments are associated with limited duration of disease control. Ponatinib is a potent KIT inhibitor with a strong activity against secondary mutations in exon 17, including the highly resistant D816 mutations of KIT. Based on the dose-depending toxicity profile we sought to evaluate the safety and activity of lower dosing (30mg) ponatinib in pretreated patients with KIT-mutant GIST. We here report safety data for the whole cohort and first efficacy data for the last line cohort within a planned interim analysis. Methods: This multicenter phase 2 trial (NCT03171389) recruited patients with advanced, unresectable GIST progressing after imatinib (Cohort A/B: absence/presence of KIT Exon 13/14 mutations by plasma sequencing) or imatinib, sunitinib and regorafenib (Cohort C). Patients were treated with 30mg oral ponatinib daily in 4-week-cycles. The primary endpoint was the clinical benefit rate at 16 weeks as measured by mRECIST1.1 criteria. Results: At the cutoff date of 31st Jan 2020, 39 patients were evaluable for safety analysis (25 male, 14 female, median age 60 (38-86) years). Median duration of treatment was 65 (14-699) days. 66.7% of all patients observed Grade 3/4 adverse events (AEs), most common were pain (10/39), hypertension (6/39), GGT or lipase increase (both 5/39), and fever (3/39). One AE of special interest was observed (myocardial infarction, rated not related to study drug) and 20/39 patients experienced at least 1 severe AE (6/39 possibly related to ponatinib). Within the last line cohort, 20 patients were evaluable for efficacy. Clinical benefit rate was 35% (CI 15.4-59.2%). Median progression-free survival was 86 days with single patients yielding long-lasting responses (75% quartile 210 days, maximum: 420 days). Conclusions: Treatment with ponatinib was tolerable at a dose of 30mg qd with a toxicity profile comparable to other TKIs used in GIST. The majority of grade 3/4 AEs were hypertension or asymptomatic increases of laboratory values and thromboembolic events were rare. In a heavily pretreated patient population that lacks alternative treatment options the clinical activity was notable. An updated analysis including predictive biomarkers will be presented. Clinical trial information: NCT03171389 .

Updated results from a randomized phase II study of cabazitaxel (CAB) versus abiraterone (ABI) or enzalutamide (ENZ) in poor prognosis metastatic CRPC.

5003 Background: The treatment for poor prognosis mCRPC includes taxanes and androgen receptor (AR) targeted therapy, however the optimal treatment is undefined. Methods: Patients (pts) with poor prognosis (liver metastases, early CRPC ( < 12 months from ADT start), and/or > 3 of 6 poor prognostic criteria (Chi et al, Annals of Oncol, 2016)) were randomized to receive CAB (Arm A) or AR targeted therapy (Arm B, ABI or ENZ by investigator choice) with cross over at progression. Primary objective was to determine the clinical benefit rate (CBR) (PSA decline ≥50% (PSA50), objective response (OR), or stable disease (SD) ≥ 12 weeks). Plasma was sampled serially for circulating tumour DNA (ctDNA). Results: 95 pts were randomized (Arm A: 45, Arm B: 50): 18% had liver mets, 88% early CRPC and 30% had > 3 of 6 poor prognostic criteria. 52% of pts had prior docetaxel, half for castration sensitive disease. Table summarizes 1st-line therapy outcomes. Baseline ctDNA fraction > 15% (median) was associated with shorter 1st-line progression-free survival (PFS) (median 2.8 vs 8.4 m, HR = 2.54, P < 0.001) and overall survival (OS) (median 14.0 vs 38.7 m, HR = 2.64, P = 0.001). ctDNA alterations in AR, TP53, PI3K pathway, RB1 and DNA repair were detected in 53%, 45%, 31%, 23%, and 21% of pts. Shorter PFS and OS were associated with AR gain (HR 2.57 (95% CI 1.63-4.06); HR 3.59, (1.9-6.69), respectively) and TP53 defects (HR 2.62 (CI 1.65-4.15); HR 3.33 (CI 1.8-6.14), respectively). Pts with concurrent defects in TP53 and RB1 had a trend for worse PFS/OS than pts with TP53 defect alone. AR rearrangements predicted to disrupt the ligand binding domain were detected in 6% of pts and had a shorter PFS (HR = 2.60 (1.11 - 6.09)) with a trend for shorter OS (HR = 2.27 (0.89 - 5.81)). Conclusions: In this poor prognosis cohort, 1st-line treatment with CAB had a higher clinical benefit rate than treatment with ABI/ENZA. Elevated ctDNA and genomic alterations in AR and TP53 were prognostic. Supported in part by Sanofi. Clinical trial information: NCT02254785. [Table: see text]

Precision oncology in sarcoma drug development: Impact of genomic matching on response, clinical benefit, and survival in sarcoma patients on phase 1 trials.

11018 Background: Genomic analyses have revealed many potentially actionable mutations across sarcoma subtypes. Whether sarcoma patients enrolled on genomically matched early phase trials have improved clinical outcomes over patients enrolled on non-genomically matched trials remains unclear. Methods: We analyzed clinical and next gen sequencing data from sarcoma patients on phase 1 trials at MD Anderson Cancer Center (MDACC) and performed logistic and Cox proportional hazards regression analyses to compare response rate (RR), median time to progression (mTTP), clinical benefit rate (CBR = CR, PR, or SD > 6 months), and median overall survival (mOS) between patients treated on genomically-matched and non-genomically matched trials. Results: Among the 406 patients with advanced sarcomas (321 soft tissue sarcoma [STS], 85 bone sarcomas) treated on phase 1 trials at MDACC from May 2006 to May 2018, median age was 53 (range 11-84), 48% were female, and patients had a median 3 prior lines of therapy (range 0-9). The most commonly treated STS subtypes were leiomyosarcoma (n = 66; 16%), liposarcoma (n = 52; 13%), GIST (n = 44; 11%), and synovial sarcoma (n = 11; 3%) and most commonly treated bone sarcomas were osteosarcoma (n = 34; 8%), chondrosarcoma (n = 28; 7%), and Ewing's sarcoma (n = 25; 6%). 23% (n = 93) of sarcoma patients treated on phase 1 trials were treated on genomically-matched trials. RR on non-genomically matched trials was 6% compared to 11% on genomically-matched trials, OR 1.97 (95% CI 0.88, 4.44), p = 0.10. Responses on genomically-matched trials were seen with novel agents targeting TRK, LRRC15, cMET, mTOR, VEGF, MDM2, KIT/PDGFRA, and FGFR. mTTP on non-genomically matched trials was 2.7 months compared to 3.7 months on genomically-matched trials, HR 0.72 (95% CI 0.57, 0.91), p = 0.0048. CBR on non-genomically matched trials was 19% compared to 41% on genomically-matched trials, OR 2.91 (95% CI 1.77, 4.80), p < 0.0001. mOS on non-genomically matched trials was 15.5 months compared to 22.1 months on genomically-matched trials, HR 0.70 (95% CI 0.50,0.98), p = 0.031. Conclusions: Enrollment on genomically-matched phase 1 trials is associated with an improvement in clinical benefit rate, time to progression, and overall survival in heavily pretreated, metastatic sarcoma patients. While RR remained low, we report the mutations associated with responses on genomically-matched trials. A prospective, biomarker-driven genomically-matched basket trial for these alterations is warranted in advanced sarcomas.

A phase II study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2- metastatic breast cancer (MBC).

1017 Background: Abemaciclib is a selective CDK4 & 6 inhibitor approved to treat HR+, HER2- MBC pts on a continuous dosing schedule as monotherapy or in combination with endocrine therapy (ET). Clinical data demonstrate abemaciclib penetrates the blood brain barrier resulting in comparable concentrations in tissues and plasma. Methods: JPBO is a Simon 2-stage trial evaluating abemaciclib in 6 pt cohorts with BM secondary to HR+ MBC, non-small cell lung cancer, or melanoma. Here, we report on HR+, HER2- MBC pts. Eligible pts had ≥1 new or not previously irradiated measurable BM ≥10mm or a progressive previously irradiated BM. Pts receiving ET at the time of enrollment were permitted to continue the same ET provided that extracranial (EC) disease was stable ≥3 months and the CNS progression occurred on the ET. Abemaciclib was orally administered 200mg BID. Primary endpoint was objective intracranial response rate (OIRR; [CR+PR]) based on Neuro-Oncology BM response assessment criteria (RANO-BM). Secondary endpoints included intracranial clinical benefit rate, PFS, and safety. Results: 58 HR+, HER2- MBC pts were enrolled and 52 pts were evaluable. Pts had a median of 4 prior systemic therapies, 75% of pts had prior chemotherapies (0-6, median of 2), and 71% of pts had prior ET (0-4, median of 1), in the metastatic setting. 50% of pts had prior whole brain radiotherapy, 39% stereotactic radiosurgery, and 8% surgical resection of BM. Median time from radiation to study enrollment was 9.4 months. Out of the 52 evaluable patients, 3 pts had a confirmed intracranial response (6% OIRR), and 38% of pts showed a decrease in the sum of their intracranial target lesions. Intracranial clinical benefit rate (CR+PR+SD persisting for ≥ 6 months) was 25%. Median PFS was 4.4 months (95% CI, 2.6-5.5). Safety and tolerability were similar to previous reports for abemaciclib. Conclusions: Abemaciclib demonstrated intracranial clinical benefit in heavily pretreated HR+, HER2- MBC pts with BM in this study. Further evaluations are ongoing to identify ABC patients with BM who might benefit most from abemaciclib. Clinical trial information: NCT02308020.