bluuebunny/crossref_metadata_2025 huggingface dataset:
First-in-human, dose-escalation, phase (ph) I trial to evaluate safety of anti-Axl antibody-drug conjugate (ADC) enapotamab vedotin (EnaV) in solid tumors.
Authors: Ameratunga Malaka , Harvey R Donald , Mau-Sørensen Morten , Thistlethwaite Fiona , Forssmann Ulf , Gupta Manish , Johannsdottir Hrefna , Ramirez-Andersen Terrie , Bohlbro Mika Linette , Losic Nedjad , Ervin-Haynes Annette L. , Lopez Juanita Suzanne , Vergote Ignace
Published: May 2019

2525

Background: Axl, a transmembrane receptor tyrosine kinase, is aberrantly overexpressed in various human cancers and associated with poor prognosis and treatment resistance. EnaV, a novel ADC of anti-Axl human IgG1 and monomethyl auristatin E, demonstrated potent anti-tumor activity in xenograft models. Methods: In a ph1 trial (NCT02988817), patients (pts) with relapsed/refractory cancer received single agent EnaV, 0.3–2.8 mg/kg once every 3 wks (1Q3W) or 0.45–1.4 mg/kg 3 times over 4 wks (3Q4W). Endpoints included dose-limiting toxicities (DLTs), adverse events (AEs) and pharmacokinetics (PK). DLTs were classed as hematological (e.g. Grade [G] 3/4 febrile neutropenia; G4 neutropenia or anemia) or non-hematological (e.g. severe skin toxicities; G3/4 neuropathy or infusion reactions; ≥G3 treatment-related AEs in first treatment cycle). Upon determining maximum tolerated dose (MTD) per arm and recommended ph2 dose (RP2D), ph2a (dose expansion) will enroll ≤297 pre-treated pts with advanced/metastatic cancer in 7 cohorts. Results: 47 pts with NSCLC (n=8), melanoma (n=9), ovarian (n=22), cervical (n=3) and endometrial (n=5) cancer enrolled in ph1 (1Q3W n=32; 3Q4W n=15). Most pts were female (87%), White (94%) and aged <65 y (66%). MTD was 2.2 mg/kg in 1Q3W arm and 1.0 mg/kg in 3Q4W arm; RP2D was 2.2 mg/kg 1Q3W. EnaV median elimination half-life: 0.9–2.2 d across doses/schedules. In 47 enrolled pts, there were 6 DLTs (Table). Most common AEs (any G; ≥40% pts) were fatigue (64%), nausea (57%), constipation (57%), diarrhea (47%), vomiting (45%) and decreased appetite (43%). 3 pts (1Q3W arm) had partial response (1 NSCLC [2.2 mg/kg dose]; 2 ovarian [1.5 and 2.4 mg/kg dose levels]). Conclusions: The RP2D of single agent EnaV in pre-treated pts with solid tumors was 2.2 mg/kg 1Q3W. EnaV had encouraging preliminary anti-tumor activity and will be evaluated in 7 ph2a expansion cohorts to further assess safety, tolerability, PK, anti-tumor activity and Axl expression. Funding: Genmab A/S. Clinical trial information: NCT02988817. [Table: see text]
A phase Ia/Ib trial of the anti-PD-L1 human monoclonal antibody (mAb), CS1001, in patients (pts) with advanced solid tumors or lymphomas.
Authors: Shen Lin , Cao Junning , Li Jin , Pan Hongming , Xu Nong , Zhang Yan , Wang Jingru , Wang Yin , Dai Hangjun
Published: May 2019

2526

Background: CS1001 is the first full-length, fully human anti-PD-L1 mAb developed by the OMT transgenic rat platform, which mirrors natural IgG4 human antibody with expected PK profiles, and may potentially reduce the risk of immunogenicity and toxicity in pts. This first-in-human Phase Ia/Ib study of CS1001 was conducted to evaluate the safety, tolerability, PK profile, and anti-tumor activity of CS1001 in pts with advanced solid tumors or lymphomas. Methods: Pts with advanced solid tumors or lymphomas were enrolled in the dose escalation Phase Ia, receiving CS1001, Q3W, IV, at escalating doses from 3, to 10, 20, 40 mg/kg and 1200 mg. Dose escalation was aided by a 3+3 dose escalation scheme. DLT was evaluated within 3 weeks after the initial dose. Pts with various tumor types were enrolled in the dose expansion Phase Ib to assess anti-tumor activity and safety, including NSCLC, esophageal carcinoma, GC, HCC, cholangiocarcinoma, etc. Safety was assessed by monitoring AEs and the associated grades per NCI CTCAE v4.03, tumor assessed per RECIST v 1.1 (solid tumors) or Lugano 2014 (lymphomas). Results: As of 30 Nov 2018, 29 pts, median age of 53 (23-75) yrs, were enrolled in Phase Ia, 3 mg/kg (N = 3); 10 mg/kg (4); 20 mg/kg (3); 40 mg/kg (3) and 1200 mg flat dose (16). A total of 20 pts discontinued treatment due to disease progression (14), death (2), withdrawal by pts (2) and AEs (2; Grade [G] 4 hepatic function abnormal and G3 pulmonary tuberculosis, both were not related to treatment). 9 pts remain on treatment. Median treatment duration was 126 (21-408+) days. No DLTs were observed. 27 of 29 pts had TRAEs with the most frequent TRAEs including anaemia (14), proteinuria (13) and blood bilirubin increased (8). G3 TRAEs include anaemia (2) and platelet count decreased (1). SAEs were reported in 6 pts and they were TRAEs. Three G4 AEs were reported: anaemia (1), hypokalaemia (1) and hepatic function abnormal (1), they were not TRAEs as determined by the investigators. irAEs occurred in 7 pts (24%). Among the 29 evaluable pts, 7 pts had PR and 8 had SD, mDoR was not reached. In Phase Ib, 97 pts were enrolled, with 65 pts on treatment and 32 pts discontinued from treatment. The most frequent reason on the discontinuation was disease progression (21). Phase Ib enrollment is still ongoing. Conclusions: CS1001 is well tolerated without DLT across tested dose levels. Evidence of anti-tumor activities was observed. Currently, 1200 mg flat dose Q3W is being explored in various tumor types in Phase Ib, and safety and efficacy results will be displayed in the presentation. Clinical trial information: NCT03312842.
Efficacy and safety of CAR19/22 T-cell “cocktail” therapy in patients with refractory/relapsed B-cell non-Hodgkin lymphoma.
Authors: Huang Liang , Wang Na , Li Chunrui , Xiao Yi , Cao Yang , Xiao Min , Zhang Yicheng , Zhang Tongcun , Zhou Jianfeng
Published: May 2019

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Background: Antigen escape relapse has emerged as a major challenge for long-term disease control post CD19-directed therapies, to which dual-targeting of CD19 and CD22 has been proposed as a potential solution. Methods: Between Mar 2016 and Jan 2018, we conducted a pilot study (ChiCTR-OPN-16008526) in 38 patients (pts), who had refractory/relapsed B-cell non-Hodgkin lymphoma (B-NHL), to evaluate the efficacy and safety of sequential infusion of anti-CD19 and anti-CD22, two single-specific, third-generation CAR19/22 T-cell “cocktail”. The cutoff date for data collection was Apr 30, 2018. Results: At a minimum follow-up of 3 months (mos), 26 of the 36 evaluable pts achieved an overall response (ORR), including 18 with a complete response (CR) and 8 with a partial response (PR). The ORR at mo 3 was consistent in different subgroups, irrespective of pathologic subtypes, cell of origin, cytogenetic or genomic aberrations. At the data cutoff, 15 of the 18 pts who had a CR at mo 3 maintained their responses, 2 of 8 pts who had a PR within 3 mos continued to have a CR without additional therapies. Collectively, the best ORR was 83.3%, with a best CR rate of 55.5% and a best PR rate of 27.8%. With a median follow-up of 5.3 mos (range, 0.4 to 16.2), the median PFS was 5.8 mos, and the median OS was not reached (NR). Pts received therapy at first relapse had better PFS than those who received therapy at the time with primary refractory diseases or at multiple relapses. Notably, pts who achieved an overall response at mo 3 (R3m) had significantly extended PFS and OS when compared with pts who did not. Repeated biopsy and IHC was conducted in 3 of the 13 pts. However, loss of CD19 or CD22 was not detected. Of the 9 pts with IgH/MYC translocation, with a median follow-up of 10.1 mos, the median PFS and median OS were NR. At data cutoff, 7 pts who had achieved R3m maintained their responses, including all the 4 pts with double-hit lymphoma. However, of the 10 pts with del(17p) or TP53 mutation, with a median follow-up of 5.3 mos (range, 2.7 to 14.5), the median PFS was 3.6 mos and the median OS was 9.9 mos. All pts experienced reversible CRS, with 21.1% were of high-grade. Neurotoxicity developed in 13.2% pts and were all low-grade. Conclusions: Our results indicated that sequential infusion of CAR19/22 T-cell is efficient and safe for pts with B-NHL. Dual antigen targeting is a promising approach to circumvent antigen loss relapse after CAR T-cell therapy. The impact of genetic subtypes and clinical parameters further underscores the critical importance of personalized immunotherapies. Clinical trial information: ChiCTR-OPN-16008526.
The phase I clinical study of CART targeting BCMA with humanized alpaca-derived single-domain antibody as antigen recognition domain.
Authors: Han Lu , Gao Quanli , Zhou Keshu , Zhou Jian , Fang Baijun , Zhang Jishuai , Li Hongjian , Song Yongping
Published: May 2019

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Background: Several phase I clinical trials already shown Chimeric antigen receptor T cells (CART) targeting BCMA has the promised effects to treat the relapsed/refractory (RR) multiple myeloma (MM), RRMM. We developed CART cells (CART-BCMA) using one single-domain antibody as recognition domain. The anti-BCMA single-domain antibody was derived from the alpaca, and humanized with the affinity of 1.14nM. The CART-BCMA use the 4-1BB and CD3ζ intracellular regions as T cell activation domain. Methods: A phase I, single arm clinical study was conducted to assess safety and efficacy of CART-BCMA. The enrolled RRMM patients had received average 10 lines of prior treatment, no matter BCMA expression level on plasma cells. Patients were subjected to a lymphodepleting regimen with Cy (300-600 mg/m2, d-5, -4) and Flu (30 mg/m2, d-5 to d-3) before CART infusion at the dose of 2-10×106 CAR+ cells/kg. The efficacy was assessed based on the IMWG Criteria, and the toxicity was graded by CTCAE 4.02. Results: As of December 31, 2018, 16 patients were infused with autologous CART-BCMA cells, and had at least 1 month of follow-up. Many patients have M protein in serum, but haven't the high percent of plasma cells in bone marrow, which are difficult to be treated by CART cells because the tumor cells are aggregated, not diffused in bone marrow. 3 patiens were diagnosed with extramedullary diseases, were evaluated as PR at D28 (tumor SPD decreasing >50%). 13 patients haven't extramedullary diseases, at D28, ORR is 84.6% (11/13); At 10 weeks, 7 patients were evaluated, ORR is 100% (sCR/CR 42.8%, VGPR 14.3% , PR 42.8% ); 5 patients reached 16 weeks, 1 relapsed, 4 kept remission. The Pt3 and Pt6 shows the CRS grade 3 or 4, other patients shows the grade 0-2 CRS, the CRS is manageable. Conclusions: Our result demonstrates the promising efficacy compared with other reported results of CART targeting BCMA, and supports further development of this anti-RRMM cellular immunotherapy. Clinical trial information: NCT03661554.
Ligand-inducible, prostate stem cell antigen (PSCA)-directed GoCAR-T cells in advanced solid tumors: Preliminary results with cyclophosphamide (Cy) ± fludarabine (Flu) lymphodepletion (LD).
Authors: Becerra Carlos Roberto , Manji Gulam Abbas , Kim Dae Won , Gardner Olivia , Malankar Aditya , Shaw Joanne , Blass Devin , Yi Xiaohui , Foster Aaron E. , Woodard Paul
Published: May 2019

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Background: Cell-surface protein PSCA is upregulated in many solid tumors and correlates with disease stage. BPX-601, an autologous T-cell product expressing a PSCA-CD3ζ CAR and a rimiducid (Rim)-inducible MyD88/CD40 co-activation switch to augment T-cell proliferation and persistence, is designed to have enhanced efficacy in solid tumors vs traditional CARs. This ongoing first-in-human study assesses safety, biologic, and clinical activity of BPX-601+Rim in PSCA+ cancers. Updated results, including those from patients (pts) who underwent LD with Flu/Cy, are presented. Methods: BP-012 is a 2-part, open-label trial. Part 1 is a 3+3 dose escalation of BPX-601 (1.25–5.0x106 cells/kg; Day [D] 0) given prior to a single, fixed Rim dose (0.4 mg/kg; D7) in pts with previously treated PSCA+ metastatic pancreatic, gastric, or prostate cancers with measurable disease. Results: As of Jan-22-2019, 15 pts have received BPX-601±Rim. Two pts at the highest cell dose received Flu/Cy for LD on D−5 to D−3 before BPX-601; LD after Flu/Cy was 96.6% and 84.3%. Thirteen pts received Cy alone on D−3; in these pts, LD ranged from 0–68.6%. Rapid cell expansion by D4 was observed in all pts with peak vector copy number 8.3-fold higher with Flu/Cy (n = 2) vs Cy LD (n = 13). Serum IP-10, IL-6 and TNFα increased > 2-fold from baseline in ≥1 pt in all Rim cohorts, with 3- to 20-fold Rim-dependent cell expansion in 6 pts. No CRS or DLTs were reported. After Rim, one Flu/Cy pt experienced a serious Grade 2 AE (encephalopathy) related to BPX-601+Rim that resolved with IV steroids; despite time-matched nonserious Grade 1 pyrexia, the pt had no other CRS symptoms. After BPX-601+Rim and ≥1 scan, best responses were 8 SD and 3 PD (1 non-evaluable). With a median follow-up of 9.8 wks, time to next treatment (tx) after BPX-601 ranged from 2.7–22.1 wks (n = 8) and ongoing tx-free intervals range from 9.1–30.1 wks (n = 4). Conclusions: BPX-601+Rim was well-tolerated with manageable safety and early evidence of enhanced CAR T-cell expansion and prolonged persistence after Flu/Cy vs Cy. Additional pts will undergo Flu/Cy LD prior to BPX-601 with single- and repeat-dose Rim. Clinical trial information: NCT02744287.
Bespoke circulating tumor DNA (ctDNA) analysis as a predictive biomarker in solid tumor patients (pts) treated with single-agent pembrolizumab (P).
Authors: Iafolla Marco Adelmo James , Yang Cindy , Dashner Scott , Xu Wei , Hansen Aaron Richard , Bedard Philippe L. , Lheureux Stephanie , Spreafico Anna , Abdul Razak Albiruni Ryan , Wu Hsin-Ta , Shchegrova Svetlana , Liu Zhihui (Amy) , Ohashi Pamela S , Torti Dax , Louie Maggie C , Sethi Himanshu , Aleshin Alexey , Siu Lillian L. , Bratman Scott Victor , Pugh Trevor John
Published: May 2019

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Background: Limited data exist in the clonal dynamics of serial ctDNA as a predictive biomarker in advanced solid tumor pts receiving immune checkpoint blockade. Methods: Pts with mixed solid tumors received single agent P (anti-PD-1) 200 mg IV Q3wks in the investigator-initiated phase II INSPIRE trial (NCT02644369). ctDNA was assayed at baseline (B) and start of cycle 3 (C3) using a pt-specific amplicon-based NGS assay (Signatera™). Samples were considered ctDNA positive if ≥2 of 16 pt-specific targets met the qualifying confidence score threshold. Results: Results of 70 pts are presented. Demographics: male 46%; median age=60 yrs (range 21–82); head and neck (20%), triple negative breast (14%) and ovarian (14%) cancers comprised the major malignancies. Median no. of P cycles=4 (range 2–35); follow up was 14m (range 2–29); RECIST responses: CR 2.9% (n=2), PR 17% (n=12), CBR (CR+PR+SD≥6 cycles) 31% (n=22), RECIST/clinical PD (n=43/10; 65%/15%). Median PFS=3.3m and median OS=17.8m. 68/70 pts had ctDNA detected at baseline (median=16/16 variants) demonstrating 97% sensitivity. Table shows correlation of ΔctDNA (ctDNAB compared to ctDNAC3) with clinical efficacy parameters, whereas ctDNAB values did not reach statistical significance. Conclusions: A strong correlation exists between ΔctDNA with OS, PFS, CBR and ORR with P, suggesting it is a potential predictive biomarker in pts with mixed solid tumors. Clinical trial information: NCT02644369. [Table: see text]
Evolution of the myeloid-derived suppressor cells in advanced breast cancer and comparative analysis with a healthy population cohort.
Authors: Palazón-Carrión Natalia , Jiménez-Cortegana Carlos , Holgado Esther , Jurado Josefina Cruz , Alonso Romero Jose Luis , Sánchez Leon María Luisa , Sanchez Margalet Victor , Nogales Esteban , Moreno Anton Fernando , Quiroga Garcia Vanesa , Andres Raquel , Santisteban Marta , Cortes Javier , Rodríguez-Rodríguez Luz Milva , Soto Gutierrez Asuncion , Cortes Mana Gion , Nieto Garcia A. , Chiesa Massimo , Bezares Susana , De la Cruz-Merino Luis
Published: May 2019

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Background: High levels of myeloid-derived suppressor cells (MDSCs) seem a negative prognostic factor in advanced breast cancer (ABC) patients (pts). Preclinical studies suggest an immunomodulatory effect of some classical anti-tumor agents through alteration of MDSCs homeostasis. We analyzed the association of MDSCs and clinical evolution of ABC pts, taking into account the systemic treatment (tx) modulation of MDSCs levels in pts from two studies (“A”: GEICAM/2015-04 PANGEA-BREAST, NCT03025880 “Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC”, and “B”: PI-0502-2014 “Peripheral blood analyses of immune response induced by 1st line tx of ABC according to clinical guidelines”). Methods: MDSCs (CD33+ CD11b+) levels were determined by flow-cytometry in peripheral blood samples at three time points (basal, at cycles 3 and 6) from: 39 HER2-negative heavily pretreated pts from study “A”, 43 non-pretreated pts (all subtypes) from study “B” and 20 women from a healthy cohort (HC), with no cancer diagnosis. MDSCs levels from the different cohorts were compared and correlated with pts with Clinical Benefit (CB: partial/complete response + disease stabilization) vs pts with Progressive Disease (PD). Results: Tx response was assessed in 33 pts (85%) from study “A” and 39 pts (91%) from study “B”. CB was observed in 11 pts (28%) from study “A” and in 34 (79%) from study “B” while PD was observed in 22 pts (56%) from study “A” and in 5 (12%) from study “B”. Basal MDSCs levels were significantly higher in ABC pts (studies “A”+”B”) than in HC (15.95 vs 0.81 cells/µl, p = 0.009). At cycle 6, MDSCs were considerably lower in pts with CB vs DP (2.90 vs 13.75 cells/µl, p < 0.001). This decrease was more pronounced in study “B” than in study “A” pts (p < 0.001 vs p = 0.074, respectively), probably due to differences in number of events, tumor subtypes and tx between both studies. Conclusions: Our results suggest that ABC pts show alterations in MDSCs and that their decrease along tx may have a positive predictive value, highlighting the importance that immune-competent status may play in the evolution of ABC. MDSCs may represent a target for therapeutic purposes in ABC.
Safety and immunobiological activity of guadecitabine sequenced with ipilimumab in metastatic melanoma patients: The phase Ib NIBIT-M4 study.
Authors: Di Giacomo Anna Maria , Covre Alessia , Finotello Francesca , Rieder Dietmar , Sigalotti Luca , Giannarelli Diana , Petitprez Florent , Lacroix Laetitia , Cutaia Ornella , Fazio Carolina , Coral Sandra , Anichini Andrea , Bock Christoph , Lowder James N. , Azab Mohammad , Fridman Wolf-Herman , Sautes-Fridman Catherine , Trajanoski Zlatko , Maio Michele
Published: May 2019

2549

Background: DNA hypomethylating agents show broad immuno-modulatory activity in neoplastic cells, and may improve the effectiveness of cancer immunotherapies. The phase 1b NIBIT-M4 trial investigated a previously unexplored therapeutic strategy using the next-generation DNA hypomethylating agent guadecitabine sequenced with ipilimumab for the treatment of advanced melanoma. Methods: Patients with unresectable Stage III/IV melanoma received escalating doses of guadecitabine 30, 45 or 60 mg/m2 subcutaneously on Days 1–5 every three weeks, and ipilimumab 3 mg/kg intravenously on Day 1 every three weeks, starting one week after guadecitabine, for four cycles. Primary endpoints were the safety, tolerability and maximum tolerated dose of treatment; secondary endpoints included immune-related disease control and objective response. Genome-wide methylation, RNA sequencing, and immunohistochemistry analyses were performed on tumor samples collected at baseline, W4 and W12. (NCT02608437). Results: 19 patients were treated and evaluable for safety and efficacy. The most common treatment-related adverse events of any grade were myelotoxicity (n = 17; 89%) and immune-related adverse events (n = 12; 63%). Grade 3 or 4 myelotoxicity occurred in 15 (79%) patients. There were no dose limiting toxicities. Rates of immune-related disease control and objective response were 8/19 (42%) and 5/19 (26%), respectively. Exploratory analyses of tumour samples (n = 8) showed that median CpG site methylation at Week 4 (74.5%) and Week 12 (75.5%) was significantly lower (p < 0.05) than at baseline (80.3%), with a median of 2454 (Week 4) and 4131 (Week 12) differentially expressed genes identified compared to baseline; among the 136 pathways significantly modulated by treatment, the most frequently activated were immune-related. Tumour immune contexture analysis (n = 11) demonstrated up-regulation of Human Leukocyte Antigen (HLA) class I molecules on melanoma cells, and an increase in CD8+, PD-1+ T cells and in CD20+ B cells in post-treatment tumour core specimens. Conclusions: Sequential guadecitabine and ipilimumab is safe and tolerable in patients with metastatic melanoma, and has promising immunological and anti-tumour activity. Clinical trial information: NCT02608437.
Phase II study of spartalizumab (PDR001) and LAG525 in advanced solid tumors and hematologic malignancies.
Authors: Uboha Nataliya Volodymyrivna , Milhem Mohammed M. , Kovacs Christina , Amin Alpesh , Magley Andrea , Purkayastha D. Das , Piha-Paul Sarina Anne
Published: May 2019

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Background: Spartalizumab and LAG525 are monoclonal antibodies targeting PD-1 and LAG-3, respectively. Dual blockade of PD-1 and LAG-3 has shown synergistic antitumor activity in preclinical models. Here we describe preliminary efficacy of spartalizumab + LAG525 across seven tumor types. Methods: Phase II, open-label, parallel-cohort study was conducted in pts with solid or hematologic malignances relapsed and/or refractory to standard-of-care therapies. Prior immunotherapy was prohibited. LAG525 (400 mg) and spartalizumab (300 mg) were dosed intravenously every 3 weeks. Primary endpoint was clinical benefit rate at 24 weeks (CBR24), assessed using a Bayesian hierarchical model-based futility analysis. Posterior probability that clinical benefit exceeds historical control (Pr) was estimated to determine futility at interim against prespecified thresholds. Results: As of January 7 2019, 76 pts received spartalizumab + LAG525; 72 pts were eligible for analysis (Table). The Pr cut-off for all arms was > 0.70. Hence, neuroendocrine tumors (NET), small cell lung cancer (SCLC) and diffuse large B-cell lymphoma (DLBCL) cohorts all met the expansion criteria with Pr of 0.971, 0.975 and 0.804 respectively. CBR24 were as follows; NET: 0.86, SCLC: 0.27, DLBCL: 0.43. Prostate, sarcoma and ovarian cohorts did not meet the expansion criterion (Pr > 0.70) but were not declared futile; enrollment was paused pending results of next analysis. Gastroesophageal (GE) cancer cohort was stopped for futility due to Pr (0.071) below the futility threshold. Conclusions: Spartalizumab and LAG525 showed promising activity in NET, SCLC and DLBCL that met expansion criteria. The GE cohort was declared futile. Remaining cohorts are paused pending further analysis. Clinical trial information: NCT03365791. [Table: see text]
Preliminary safety, efficacy, and pharmacokinetics (PK) results of KN046 (bispecific anti-PD-L1/CTLA4) from a first-in-human study in subjects with advanced solid tumors.
Authors: Coward Jermaine , Ganju Vinod , Behzadigohar Ramin , Kwong Kenneth , Xu June , Van Hardy , Kong Paul , Yang Fei , Chen Lisa , Guo Kangping , Liu Mei , Zhu Danming , Donato Lara Kristina , Xu Ting , Richardson Gary Edward
Published: May 2019

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Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of Tregs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( > 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.
Antitumor activity and safety of MK-1308 (anti-CTLA-4) plus pembrolizumab (pembro) in patients (pts) with non-small cell lung cancer (NSCLC): Updated interim results from a phase I study.
Authors: Perets Ruth , Yoh Kiyotaka , Kim Dong-Wan , Bar Jair , Ahn Myung-Ju , Nagrial Adnan , Satouchi Miyako , Rasco Drew W. , Lee Dae Ho , Spigel David R. , Kotasek Dusan , Gutierrez Martin , Niu Jiaxin , Siddiqi Shabana , Chain Anne , Butts Brent D. , Li Xiaoyun Nicole , Cyrus Jobin , Altura Rachel , Cho Byoung Chul
Published: May 2019

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Background: An ongoing multicenter, open-label, phase 1 study of the anti–CTLA-4 antibody MK-1308 in combination with pembro in advanced solid tumors (NCT03179436) revealed a manageable safety profile and promising efficacy in pts with first-line (1L) advanced NSCLC. Data from a larger sample size and longer follow-up are presented. Methods: In dose escalation (DE), pts with advanced solid tumors received MK-1308 by IV administration at 25, 75, or 200 mg Q3W ×1 cycle then in combination with pembro 200 mg Q3W ×4 cycles followed by pembro monotherapy (up to 35 cycles). In dose confirmation (DC), pts with 1L advanced NSCLC received MK-1308 at 25 or 75 mg—Q3W or Q6W—plus pembro 200 mg Q3W (up to 35 cycles). Safety (all treated pts), efficacy (subset of 1L NSCLC pts), pharmacokinetics (PK, all treated pts), and PD-L1 tumor expression (subset of 1L NSCLC pts) were analyzed. Results: 213 pts were treated (DE, n=39; DC, n=174). All pts were included in the safety analyses (median follow-up, 8 months); 113 pts from DC were included in the efficacy analyses (median follow-up, 8 months). PK showed a dose-dependent increase in MK-1308 exposure. Neither target dose-limiting toxicity (≥10%) nor maximum tolerated dose were reached for MK-1308 plus pembro; however, toxicity increased with increasing MK-1308 dose and shorter dosing intervals. Treatment-related adverse events grade ≥3 occurred at the lowest rates at 25 mg Q3W in DE (0%) and 25 mg Q6W in DC (25%) and at the highest rates at 200 mg Q3W in DE (75%) and 75 mg Q3W in DC (50%). Efficacy was observed at all MK-1308 dose levels and intervals: confirmed ORR per RECIST 1.1 by central review in 1L advanced NSCLC was 39% at 25 mg Q3W, 33% at 25 mg Q6W, 22% at 75 mg Q6W, and 25% at 75 mg Q3W; 6-month PFS and OS rates are 67% and 89% for the 25 mg Q6W arm. There was a 25% ORR in PD-L1–negative 1L advanced NSCLC pts. Conclusions: MK-1308 plus pembro was generally well tolerated with no unexpected toxicity and conferred encouraging antitumor activity in 1L advanced NSCLC pts. Efficacy, safety, and PK data suggest that 25 mg given Q6W is the recommended phase 2 dose for MK-1308 in combination with pembro. Clinical trial information: NCT03179436.
IOLite: Multipart, phase 1b, dose-finding study of the PD-1 inhibitor dostarlimab in combination with the PARP inhibitor niraparib ± bevacizumab (bev), or with platinum-based chemotherapy ± bev for advanced cancer.
Authors: Gabrail Nashat Y. , Bessudo Alberto , Hamilton Erika Paige , Sachdev Jasgit C. , Patel Manish R. , Rodon Ahnert Jordi , Evilevitch Lena , Duncan Meghan , Guo Wei , Lu Sharon , Dezube Bruce Jeffrey , Yap Timothy A
Published: May 2019

2560

Background: Novel combinations of drugs may overcome resistance in patients (pts) with solid tumors who had progressed on standard therapy. Methods: IOLite (NCT03307785) is a multicenter, open label, multipart study to determine dosing and evaluate safety and efficacy of dostarlimab in combination with approved therapies in pts with advanced solid tumors. Pts were enrolled in each part based on tumor histology, prior treatment (tx) history, and physician preference. Primary endpoint is dose-limiting toxicities (DLTs) deemed as tx-related per investigator, and safety and tolerability of the combination. Tumor responses were assessed per RECIST v1.1. Results: Parts A-D (see Table) are fully enrolled. One complete response was reported in part B (endometrial); confirmed partial responses in part A (ovarian, small cell lung [SCLC], gastrointestinal stromal [GIST]); part B (breast [2], bladder, SCLC); part C (prostate, fallopian tube), and part D (endometrial, non-SCLC). Stable disease was reported in part A (colorectal, prostate [2], breast, GIST, gastric); part B (SCLC, squamous cell, head and neck, prostate); part C (pancreatic, ovarian, GIST, breast [2], liver, endometrial); part D (ovarian, head & neck, cholangiocarcinoma). At data cutoff, 24 pts remain on treatment. PK’s of dostarlimab and niraparib (nir) were not altered by any of the combination agents tested. Conclusions: Dostarlimab is well tolerated in combination with nir ± bev, or carbo-pac ± bev. Preliminary efficacy data show responses in various histologies. No new safety signals were identified. Clinical trial information: NCT03307785. [Table: see text]
Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors.
Authors: Patel Manish R. , Falchook Gerald Steven , Wang Judy Sing-Zan , Rodrigo Imedio Esteban , Kumar Sanjeev , Motlagh Pejvack , Miah Kowser , Mugundu Ganesh M. , Jones Suzanne Fields , Spigel David R. , Hamilton Erika Paige
Published: May 2019

2562

Background: Adavosertib (AZD1775; A) is a highly selective inhibitor of WEE1. This Phase I study (NCT02617277) investigated a range of doses and schedules for oral A plus IV durvalumab (DV), a human monoclonal antibody targeting PD-L1, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Four 28-day schedules (Sch) were evaluated with pts receiving DV 1500 mg on day (d) 1 of each schedule (Table). Patients continued treatment if they showed clinical benefit in the absence of any discontinuation criteria. Pts received A monotherapy for PK analysis prior to the start of combination therapy in Sch B, C (d –7 to –5) and D (d –9 to –5). MTD was determined using a 3+3 dose-escalation cohort design. Predefined dose-limiting toxicities (DLTs) were evaluated during the first cycle of study treatment. Results: 54 pts received A (most common primary tumor sites: colon, 19%; lung, 13%; breast, 11%). The most common grade ≥3 AEs were fatigue (15%), diarrhea (11%) and nausea (9%). DLTs were nausea (n = 2) and diarrhea (n = 1). 7 pts (13%) had A-related SAEs, including reversible and confounded drug-induced liver injury (Sch B 125 mg and Sch C; 1 each). Disease control rate (DCR) for the total cohort was 36%. Preliminary PK at 150 mg BID suggests adequate coverage for cell kill activity and no drug–drug interaction. Conclusions: The MTD/RP2D was A 150 mg BID (3 d on, 4 d off; treatment d 15–17, 22–24) with DV 1500 mg (d 1 Q4W); safety profile was considered acceptable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT02617277. [Table: see text]
Early incidence of immune-related adverse events (irAEs) predicts efficacy in patients (pts) with solid tumors treated with immune-checkpoint inhibitors (ICIs).
Authors: Morehouse Chris , Abdullah Shaad Essa , Gao Chen , Dar Mohammed M. , Ranade Koustubh , Higgs Brandon W.
Published: May 2019

2563

Background: Treatment with ICIs can manifest immune-related adverse events (irAEs), which have correlated with clinical outcomes in certain tumors. However, timing of these events and how early irAEs correlate with outcomes is unclear. We assessed whether early occurring irAEs could predict survival in pts treated with durvalumab (D), an anti-PDL1 and combined with tremelimumab (D+T), an anti-CTLA4 in two clinical studies. Methods: Two phase 2 non-randomized clinical trials evaluating D (D4190C00001 (1108), N=756; available data per internal data re-use policy) or D+T (D4190C00010 (C10), N=327; expansion and ICI naïve cohorts) in multiple solid tumor types were analyzed. Prevalence of pts experiencing irAEs, regardless of grade was 30% and 59% in studies 1108 and C10, respectively, with most frequent including dermatitis/rash (25%), thyroid (15%), diarrhea/colitis (14%), and pancreatic enzyme elevation (5%). Overall survival (OS) was correlated with irAE timing prior to 6, 8, 12, 16, 20 and 24 weeks following D or D+T treatment. Kaplan Meier and log-rank analyses were used. Results: In both studies, pts who experienced at least one irAE by study completion had improved median OS (mOS, 1108: 23.1 mos [18.2, 26.9]; C10: 16.3 mos [12.5, 31.4]) relative to those who experienced none (1108: 6.3 mos [5.4, 7.3]; C10 4.6 mos [3.3, 6.1]). Median time (weeks) to first and second irAE occurred earlier in C10 compared to 1108, 3.9 vs. 5.6 and 6.9 vs. 10.1, respectively. When associating timing of irAEs with survival, there was a significant differential in mOS at each time interval evaluated between pts with at least one irAE and those with none, with differentiation at 6 weeks and maximal survival benefit at 24 weeks following treatment with D or D+T (Table). Conclusions: Early occurrence of irAEs may be predictive of survival benefit in pts treated with D or D+T. OS by 1+ or no irAE(s) occurring up to 6 or 24 weeks post treatment. [Table: see text]
Association between past medical history (PMH) of autoimmune events and adverse events of special interest (AESI).
Authors: Brewer Jamie Renee , Maher Virginia Ellen , Weinstock Chana , Agrawal Sundeep , Brave Michael Holman , Ning Yang-Min , Singh Harpreet , Suzman Daniel L. , Xu James , Ibrahim Amna , Beaver Julia A. , Pazdur Richard
Published: May 2019

2565

Background: PD-1/L1 inhibitor therapy has become the standard of care for many advanced solid tumors. A notable limitation of PD-1/L1 inhibitor therapy is the concern for AESI that are likely to be immune related. It is unclear whether a history of autoimmune events is a predisposing risk making these adverse events more likely. We aimed to evaluate the association between autoimmune-associated PMH and AESI on PD-1/L1 inhibitors. Methods: We pooled data across seven pivotal trials for PD-1/L1 inhibitors in urothelial cancer (UC) identifying patients with AESI submitted from 2016 - 2017. AESI were determined using a pooled preferred term list for each trial. Information collected from trials included PMH, AESI events and toxicity grade. Results: In total, 1747 immunotherapy treated patients were identified, with 1068 (61%) having an AESI and 277 (26%) having an autoimmune-related PMH. The most common autoimmune-associated events in the PMH were thyroid disorders (64%), asthma (23%), atopic dermatitis/eczema (6%), irritable bowel syndrome (5%), and psoriasis (4%). AESI occurred in 68% of patients with an autoimmune-related PMH and 60% of patients without an autoimmune-related PMH. The most common AESI in patients with an autoimmune-related PMH were diarrhea (35%), rash (27%), renal disorder (27%), and pruritis (23%). The most common AESI in the general trial population were diarrhea (28%), pruritis (26%), rash (25%), increased creatinine (14%), and elevated AST and ALT (10% and 9%). The majority of events were Grade 1-2 (87% in patients with an autoimmune-related PMH and 84% in the general trial population). Conclusions: Pooled clinical trial data shows a slight numeric increase in AESIs in patients with autoimmune-associated PMH. Limitations include potential lack of consistency of PMH documentation and adverse event reporting. There did not appear to be a pattern of association between PMH and type of AESI event. Grades of AESI events in the population with autoimmune-associated PMH were similar to the general trial population. This suggests that PD-1/L1 inhibitors may be safely administered to patients with UC and a PMH of some autoimmune-associated events. Further exploration is needed.
A phase II clinical trial of ipilimumab/nivolumab combination immunotherapy in patients with rare upper gastrointestinal, neuroendocrine, and gynecological malignancies.
Authors: Klein Oliver , Kee Damien , Markman Ben , Chang Lee Rachael , Michael Michael , Mileshkin Linda R. , Scott Clare L. , Linklater Richelle , Menon Sid , Tebbutt Niall C. , Palmer Jodie , Behren Andreas , Cebon Jonathan S.
Published: May 2019

2570

Background:
Patients (pts) with rare cancers represent an unmet medical need and have an inferior overall survival compared to patients with more common malignancies. Due to their low frequency, no therapies, including immunotherapies, have systematically been investigated in this population. Ipilimumab (ipi)/Nivolumab (nivo) combination treatment has demonstrated significant clinical activity in pts with advanced melanoma and renal cell carcinoma and response rates with this regimen are higher compared to single agent anti-PD-1 therapy. This phase II study assessed the efficacy and safety of ipi/nivo in rare cancer pts.
Methods:
60 pts with advanced rare upper gastrointestinal (GI), neuroendocrine (NE) and gynaecological (GY) malignancies were enrolled in 3 cohorts. Patients received nivo 3mg/kg and ipi 1mg/kg every 3 weeks for four doses, followed by nivo 3mg/kg every 2 weeks. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR), CR, PR and SD. Exploratory endpoints include correlation of efficacy with relevant biomarkers including PDL1 status and tumour mutation burden.
Results:
42 pts have so far undergone restaging, 11 pts clinically progressed prior to their first restaging scan. 50 pts have received prior therapy (1-5 lines). Objective responses have been observed in a range of different malignancies.
Clinical trial information: NCT02923934.
Grade 3/4 immune related adverse events were detected in 31% of pts. The results of correlative biomarker studies will be presented at the meeting.
Conclusions:
Ipi/Nivo combination treatment has efficacy in a wide range of advanced rare malignancies. Immune related toxicity is in keeping with previously reported clinical trials using the same dosing regimen.

# pts
53
GI (16)
NE (20)
GY (17)

ORR
32%
31%
25%
41%

3 pts Cholangioca
3 pts Atypical bronchial carcinoid
1 pt Ovarian clear cell ca

2 pts Gallbladder ca
1 pt Pancreatic NET
1 pt Ovarian germ cell tumor

1 pt Adrenocortical ca
1 pt Uterine clear cell ca

1 pt Uterine carcinosarcoma

1 pt Uterine leiomyosarcoma

1 pt Vaginal SCC

1 pt low grade serous ovarian ca

SD
36%
19%
55%
29%

CBR
68%
50%
80%
70%

PD
32%
50%
20%
30%
Outcomes after early initiation of nonsteroidal immunosuppressive therapy in patients with immune checkpoint inhibitor-induced colitis.
Authors: Wang Yinghong , Abu-Sbeih Hamzah , Ali Faisal , Altan Mehmet , Dadu Ramona , Jazaeri Amir A.
Published: May 2019

2571

Background: Current treatment guidelines for immune-mediated colitis (IMC) recommend 4 to 6 weeks of steroids as first-line therapy, followed by nonsteroidal immunosuppressive therapy (NSIST) (infliximab or vedolizumab) in patients who do not respond to steroids. We assessed the effect of early NSIST introduction and number of NSIST infusions on clinical outcomes. Methods: We performed a retrospective review of patients with IMC who received NSIST between January and December 2018. Logistic regression analyses were used to assess associations between clinical features and outcomes of IMC (Table). Results: Of the 1,459 patients who received immune checkpoint inhibitor, 179 developed IMC of any grade; 84 of them received NSIST. Of the 84 patients who received NSIST, 79% were males with mean age of 60. Compared with patients who received NSIST >10 days after IMC onset, patients who received early NSIST (≤10 days) required fewer hospitalizations ( P=0.03), experienced steroid taper failure less frequently ( P=0.03), had fewer steroid tapering attempts ( P<0.01), had a shorter course of steroid treatment ( P=0.09), and had a shorter duration of symptoms ( P<0.01). Risk factors of IMC recurrence after weaning off steroids included: 1) needing multiple hospitalizations ( P<0.01), 2) experiencing steroid taper failure after NSIST ( P=0.02), 3) receiving infliximab rather than vedolizumab ( P=0.02), 4) receiving fewer than three infusions of NSIST ( P=0.02), 5) having higher fecal calprotectin levels after NSIST ( P=0.01), and 6) receiving a longer course of steroids ( P=0.02), hospitalization ( P<0.01) and IMC symptoms ( P<0.01). Unsuccessful weaning from steroids after NSIST was associated with high IMC grades ( P<0.01); multiple hospitalizations ( P<0.01); steroid-resistant IMC ( P<0.01); long interval from IMC to NSIST initiation ( P=0.01); and long duration of steroids ( P<0.01), IMC symptoms ( P<0.01), and hospitalization ( P<0.01). Conclusions: NSIST should be introduced early in the disease course of IMC instead of waiting until failure of steroid therapy or steroid taper. Patients who received three or more infusions of NSIST had more favorable clinical outcomes.
Feasibility and toxicity of neoadjuvant nivolumab with or without ipilimumab prior to extensive (salvage) surgery in patients with advanced head and neck cancer (the IMCISION trial, NCT03003637).
Authors: Zuur Charlotte L. , Elbers Joris B. W. , Vos Joris L. , van der Leun Anne , Qiao Xiaohang , Karakullukcu Baris , van den Brekel Michiel W. M. , Tan Bing , Jasperse Bas , Vogel Wouter V. , Smit Laura , Willems Stefan M. , van Tinteren Harm , Al-Mamgani Abrahim , Nijkamp Jasper , Schumacher Ton N. , Blank Christian U. , De Boer J. P. , Haanen John B. A. G.
Published: May 2019

2575

Background: surgery w/wo adjuvant radiotherapy (RT) for (recurrent) advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% 5-year OS, indicating the need for novel treatment options. In recurrent metastatic HNSCC nivolumab nearly tripled the 2-year OS. Aiming at improving clinical outcome in advanced HNSCC in a curative setting, we tested the feasibility of nivolumab ± ipilimumab neoadjuvant to (salvage) surgery w/wo RT. Methods: investigator-initiated phase-IB/II trial to assess feasibility of neoadjuvant nivolumab monotherapy (240 mg in week 1&3: arm-A) or in combination with ipilimumab (1 mg/kg in week 1: arm-B) before surgery (≤ week 5) w/wo RT for advanced HNSCC. Results: 12 patients were included (3+3 design, both arms) in phase-IB of this study; 7/12 (58%) patients had pre-existent moderate-to-severe comorbidities (ACE-27). All patients were HPV negative. All patients received surgery as planned (25-33 days after start of immunotherapy) with no unexpected wound healing problems. In both groups, 4 patients (67%) experienced immune-related toxicity: grade 1-2 (n = 4) and grade 3-4 (n = 1; colitis) in arm-A; grade 1-2 (n = 5) and grade 3-4 (n = 2; colitis and elevated liver enzymes) in arm B. Immune-related toxicity was managed with prednisone (n = 2) and infliximab (n = 1). There was 1/6 (12.5%) pathological response in arm-A (1 near complete response, nCR) and 3/6 (50%) in arm-B (1x partial response and 2x nCR). No patients with nCR had a recurrence at follow-up (median 10 months). Preliminary data (mutational load will be added) show increased H7-B3 gene expression in non-responders before treatment, and increased endothelial cell and NK cell gene expression in responders post-treatment. Overall, in these 12 patients, neoadjuvant ipilimumab + nivolumab resulted in a significant increase in immune-related gene expression when compared to nivolumab only, irrespective of treatment response. Conclusions: neoadjuvant ipilimumab + nivolumab can safely be administered prior to major surgery for advanced HNSCC. Efficacy is promising and will be further evaluated in the phase-II trial continuation. Clinical trial information: NCT03003637.
Patient survival with immune checkpoint inhibitors and targeted agents in phase 1 trials: A propensity score weighted analysis.
Authors: Gardeazabal Itziar , Matos Ignacio , Hierro Cinta , Azaro Analia , Viaplana Cristina , Brana Irene , Villar Maria Vieito , Saavedra Omar , Villacampa Guillermo , Martin-Liberal Juan , Ochoa de Olza Maria , Verdaguer Helena , Oliveira Mafalda , Argiles Guillem , Navarro Alejandro , Carles Joan , Muñoz-Couselo Eva , Tabernero Josep , Dienstmann Rodrigo , Garralda Elena
Published: May 2019

2580

Background: There have been important changes in early drug development units with an unprecedented increase of immune-oncology (IO) trials. Currently at the Vall d’Hebron Institute Oncology (VHIO) close to 50% of our Phase 1 trials (Ph1t) portfolio includes IO drugs, while from 2011 to 2015 more than 80% of our trials assessed targeted agents (TA). We wanted to investigate whether this swift had a positive impact on patient (pts) outcome. Methods: We performed a retrospective analysis of the pts treated with IO and TA at VHIO Ph1t Unit from Jun’11 to May’18. Only patients treated with IO in ≥ 2nd line were included (and without an approved IO therapy as per standard-of-care) and those with TA classified as tiers II-III-IV by the ESMO scale for clinical actionability of molecular targets ESCAT (which also represents unapproved indications). The aim of this study was to compare overall survival (OS) for the two cohorts. Given the non-randomized nature of the study a propensity score weighting (PSW) was used to control for selection bias in treatment effect estimation. Results: Out of 545 eligible pts, 281 (51.5%) received TA and 264 (48.5%) IO, with unadjusted median OS (mOS) of 7.7 months (m) and 9.2m, respectively. In univariate analysis, OS was associated with tumor type, number of previous treatment lines, regimen (monotherapy vs combination), and clinical-laboratory prognostic factors (Vioscore: albumin < 3.5 g/dl; LDH > upper limit of normal; neutrophil/[leukocytes minus neutrophils] ratio (dNLR) > 3; more than 2 sites of metastasis; and presence of liver metastasis) (p < 0.05). After adjusting for these factors in a PSW model, the IO group showed statistically significant longer OS with HR = 0.75 (CI95% 0.65 – 0.86, p < 0.0001). The In a stratified analysis by tumor type we found no significant heterogeneity in the relative benefit of IO over TA. Conclusions: In real world data from our Ph1t population, treatment with IO was associated with longer OS than treatment with TA, even after adjusting for known prognostic factors and treatment selection biases. These results suggest that the likelihood of patient benefit with IO therapies in Ph1t is increasing.