bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: Safety and preliminary efficacy in combination with anti-PD-1 agent.
Authors: Adusumilli Prasad S. , Zauderer Marjorie Glass , Rusch Valerie W. , O'Cearbhaill Roisin , Zhu Amy , Ngai Daniel , McGee Erin , Chintala Navin , Messinger John , Cheema Waseem , Halton Elizabeth , Diamonte Claudia , Pineda John , Vincent Alain , Modi Shanu , Solomon Stephen Barnett , Jones David Randolph , Brentjens Renier J. , Riviere Isabelle , Sadelain Michel
Published: May 2019

2511

Background: We conducted a phase I dose escalation trial of first-in-human autologous chimeric antigen receptor (CAR) T-cell immunotherapy targeting mesothelin (MSLN), a cell-surface antigen that is highly expressed in pleural cancers- malignant pleural mesothelioma (MPM) and metastatic lung and breast cancers. Methods: A single dose of CD28-costimulated MSLN CAR T cells with the I-caspase-9 safety gene was administered intrapleurally in patients with MSLN-expressing pleural tumors. Following a 3+3 design, patients were treated in dose escalating cohorts (dose range 3E5 to 1E7 CAR T cells/kg) following IV cyclophosphamide lymphodepletion (first 3 patients did not receive cyclophosphamide). A subset of MPM patients received subsequent anti-PD-1 therapy, off-protocol, which we have shown to prolong CAR T-cell functional persistence in preclinical models. Results: Twenty patients (18 MPM, 1 lung cancer, 1 breast cancer) were treated (prior lines of therapy 1–8, 35% received ≥3 lines of therapy). No CAR T-cell–related toxicities higher than grade 1 were observed. Intense monitoring for on-target, off-tumor toxicity by clinical (chest or abdominal pain), radiological (CT/PET or echocardiogram for pericardial effusion, ascites), laboratory (troponin elevation), and EKG evaluation found no evidence of toxicity. Fourteen MPM patients received subsequent anti-PD1 therapy (1–21 cycles, pretreatment tumor PD-L1 < 10% in all patients except one), with 1 patient developing grade 3 pneumonitis that responded to steroid treatment. CAR T cells were detected in the peripheral blood of 13 of 14 patients (1-39 weeks). At data cut-off date (Jan 31, 2019), among 14 MPM patients that received combination therapy (follow-up 13-77 weeks, median 31 weeks), best responses included 2 patients with complete metabolic response on PET (62 and 39 weeks ongoing); 5 partial responses and 4 stable disease by investigator assessment. Conclusions: Intrapleurally administered MSLN-targeted CAR T cells were safe. Encouraging antitumor activity of MSLN-targeted CAR T-cell therapy was observed when combined with anti-PD1 therapy and shows promise for future development of this approach. Clinical trial information: NCT02414269.
A phase I study of ALX148, a CD47 blocker, in combination with established anticancer antibodies in patients with advanced malignancy.
Authors: Chow Laura Quan Man , Gainor Justin F. , Lakhani Nehal J. , Chung Hyun Cheol , Lee Keun-Wook , Lee Jeeyun , LoRusso Patricia , Bang Yung-Jue , Hodi F. Stephen , Fanning Philip , Zhao Yonggang , Jin Feng , Wan Hong , Pons Jaume , Randolph Sophia , Messersmith Wells A.
Published: May 2019

2514

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host’s immune response. ALX148 (A) is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. ALX148 is well tolerated in combination with pembrolizumab (P) or trastuzumab (T) with no maximum tolerated dose (MTD) identified (ASCO 2018 #3068, SITC 2018 #P335). Safety and antitumor activity of ALX148 (10 mg/kg QW) in combination with T or P are reported in patients (pts) including those with anti-HER2 or checkpoint inhibitor (CPI) relapsed/refractory diseases. Methods: Patients with malignancy including non-small cell lung cancer (NSCLC: CPI resistant/refractory or PD-L1 tumor proportion score <50%) and head and neck squamous cell carcinoma (HNSCC: progressed on platinum therapy) received A+P. Patients with HER2 malignancy including gastric/gastroesophageal junction (GEJ) cancer (progressed on T + fluoropyrimidine-based therapy) received A+T. Safety, response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed. Preliminary data from fully enrolled cohorts are reported as of 20 Jan 2019 (safety)/28 Jan 2019 (efficacy). Results: Seventy-nine pts received A+P (All, n=50; NSCLC, n=23; HNSCC, n=20) or A+T (All, n=29; Gastric/GEJ, n=23) as of data cutoff. Forty-seven pts reported mostly low grade treatment related adverse events. The most common were fatigue (11%), AST increase (9%), ALT increase (8%), anemia (8%), and platelets decreased (6%). In select tumor histologies, anticancer activity was observed in initial response-evaluable pts [NSCLC (n=23) 1PR, 8SD; HNSCC (n=17) 3PR, 4SD; and Gastric/GEJ (n=21) 4PR, 6SD]. Preliminary results indicate favorable ALX148 PK and CD47 target occupancy profiles, and positive effects on tumor infiltrating immune cells. Results will be updated at presentation. Conclusions: ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics to date. Objective responses were observed in patients with late line NSCLC, HNSCC, and Gastric/GEJ, including disease relapsed/refractory to prior CPI and HER2-targeted therapies. Clinical trial information: NCT03013218.
Distinct immunogenomic properties of melanomas with stable disease as best response to immune checkpoint blockade (ICB).
Authors: Vokes Natalie , Margolis Claire , Liu David , Schilling Bastian , Schadendorf Dirk , Van Allen Eliezer Mendel
Published: May 2019

2515

Background: ICB has improved survival in melanoma. Patients with stable disease (SD) as best treatment response represent an intermediate response phenotype whose biology has been incompletely characterized. Methods: Whole exome and transcriptome sequencing from pre-treatment tumors in melanoma patients treated with ICB (anti-CTLA-4 and/or anti-PD-1) were assembled and uniformly analyzed (WES n = 293; WES+RNA-seq n = 159). RECIST (v1.1) was used to determine complete or partial response (CR/PR; n = 94), SD (n = 42), or progressive disease (PD; n = 157). Gene set enrichment analysis (GSEA) was performed on 50 “hallmark” gene sets to identify pathways differentially expressed in patients with SD. CIBERSORT was used to infer relative proportions of 22 immune cell types in each sample. Mutation antigenicity was determined by calculating patient-specific mutation affinity for MHC class I peptides. Results: GSEA identified enrichment of multiple immune-related gene sets in SD tumors, including TNF-α signaling and interferon-ɣ response (FDR q < 0.1, SD vs CR/PR and SD vs PD). SD tumors had higher HLA and antigen presentation pathway expression, and increased cytolytic T cell activity compared to CR/PR and PD. CIBERSORT analysis identified higher total immune infiltrate in SD patients compared to CR/PR and PD (Mann-Whitney U p = 0.03 and p < 0.001, respectively) but not in patients with CR/PR vs PD (p = 0.124). However, checkpoint expression, including PD-1, PD-L1, and LAG3, was also higher in SD patients. Mutation load did not differ between SD and CR/PR or PD patients (SD median 2.87 vs CR/PR median 7.98, Mann-Whitney U p = 0.104; PD median 3.42, p = 0.210). However, SD patients had more antigenic passenger mutations (SD vs CR/PR, p = 0.001; vs PD, p < 0.001); there was no difference in antigenicity of driver mutations. Conclusions: Pre-treatment melanomas from patients with SD contain more antigenic passenger mutations and demonstrate a global increase in immune signaling. This may describe a subset of patients with pre-existing dysfunctional immune response that is minimally responsive to ICB. Further characterization of the tumor-immune interaction in these patients may inform improved interventions.
Impact of bridging chemotherapy on clinical outcome of CD19 CAR T therapy in adult ALL.
Authors: Perica Karlo , Flynn Jessica , Curran Kevin Joseph , Wang Xiuyan , Halton Elizabeth , Diamonte Claudia , Pineda John , Bernal Yvette , Gonen Mithat , Riviere Isabelle , Sadelain Michel , Brentjens Renier J. , Park Jae Hong
Published: May 2019

2520

Background: Autologous chimeric antigen receptor (CAR) T cell therapy has shown to be effective in CD19+ relapsed or refractory (R/R) B-ALL but requires a 2-4 week period of cell processing and manufacture. During this “bridging period,” patients are vulnerable to disease progression and complications. We sought to characterize bridging strategies in our published study of CD19 CAR T cell therapy in adults with R/R ALL (Park et al., NEJM, 2018). Methods: We performed a retrospective review of adult patients with R/R ALL treated with 19-28z CAR T therapy at MSKCC. Bridging therapy was defined as any therapy given from trial enrollment to cell infusion and classified as either high intensity (remission-inducing or myelosuppressive regimens, eg hyper-CVAD or high-dose cytarabine based regimens) or low intensity (maintenance and/or less myelosuppressive regimens, eg POMP, Blinatumomab, TKI). Results: Of 53 patients who received CAR T cell infusion, 19 were bridged with a high intensity regimen and 34 with a low intensity regimen. There was no difference in number of prior therapies, pre-bridging chemotherapy disease burden, and prior transplant status between groups. High intensity therapy was associated with a higher rate of Gr3-4 infectious complications during the bridging period (78% vs 32%, p < 0.002 by Fisher’s Exact) but not with response to bridging or CAR T cell therapy, relapse free survival, post-CAR Gr3-4 cytokine release syndrome (CRS) or neurotoxicity (NT). Patients in both groups who converted from morphologic to molecular disease during bridging (n=9) had a decreased rate of eventual severe CRS (0% vs 41%, p=0.01) or NT (0% vs 55%, p <0.01) compared to patients with persistent morphologic disease. In all patients enrolled on trial (n=83), use of high compared to low intensity bridging was not associated with higher rates of successful CAR T cell infusion (63% vs 79%, p>0.05) or a combined endpoint of CAR T cell infusion or alternative therapy including transplant (80% vs 86%, p> 0.05). Conclusions: High intensity bridging therapy is associated with a high risk of infectious complications without a clear benefit in outcome in R/R ALL receiving CD19 CAR T cells. Selection of bridging regimen therefore requires consideration of previous treatments and patient status to maximize the efficacy and safety. Clinical trial information: NCT01044069.
A phase I study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of JNJ-64457107, a CD40 agonistic monoclonal antibody, in patients (pts) with advanced solid tumors.
Authors: Calvo Emiliano , Moreno Victor , Perets Ruth , Yablonski-Peretz Tamar , Fourneau Nele , Girgis Suzette , Guo Yue , Hellemans Peter , Hokey David , Pendas Franco Natalia , Xia Qi , Geva Ravit
Published: May 2019

2527

Background: JNJ-64457107 (JNJ-107) is an agonistic human monoclonal (IgG1) antibody targeting CD40, a novel target for anti-tumor immunotherapy with a central role in adaptive and innate immunity. Methods: JNJ-107 was administered intravenously Q2W in treatment cycles of 28 days. Dose escalation was pursued with (w) and without (wo) pre-infusion steroids for mitigation of infusion related reactions (IRRs). Dose-limiting toxicity (DLT), safety, PK, PD and antitumor activity were evaluated. Results: 95 pts of age 18-80 years (median 59) were enrolled in 7 cohorts (n = 50, 75µg/kg – 2000 µg/kg) w/steroids and 5 cohorts (n = 45, 75 µg/kg – 1200 µg/kg) wo/steroids and received 1-26 (median 3) cycles of JNJ-107. Two DLTs occurred: Grade (G) 3 headache lasting 5 days at 1200 µg/kg w/steroids and G3 ALT/AST + G2 bilirubin increase at 1200 µg/kg wo/steroids. Most frequent adverse events (≥20%) were pyrexia (41%), fatigue (39%), pruritus (39%), headache (26%), chills (26%), nausea (22%) and rash (21%). IRRs were reported in 51% of pts (G1-G2 50%, G3 1%). Most commonly reported IRRs (≥10%) were pruritus (31%), rash (15%), chills (13%) and flushing (12%). Cetirizine and Montelukast premedication during dose escalation wo/steroids significantly reduced IRRs. Preliminary PK of JNJ-107 suggest target mediated drug disposition with rapid decline in serum concentrations (half-life of ~13h at 600 µg/kg and ~ 24h at doses ≥1200 µg/kg). Dose proportional increase in Cmax and AUC(last) was observed at doses ≥1200 µg/kg and more than dose proportional increase was seen at lower doses. PD of JNJ-107 demonstrated dose-independent reduction in peripheral blood B cells recovering in a dose-dependent manner. MCP-1, IP-10, MIP-1a, and MIP-1b cytokines showed high-level responses with cytokine/chemokine secretion kinetics consistent, but not confirmatory, for activation of antigen presenting cells. IFNg, TNF, and IL-8 showed moderate responses reflecting downstream T cell activation. Other tested cytokines were at low levels. A partial response lasting 9.2 months was observed in 1 pt with renal cell cancer. 13 (14%) and 10 (11%) pts showed stable disease lasting ≥3 months and ≥ 6 months, respectively. Conclusions: The CD40 agonist JNJ-107 has a manageable safety profile with favorable PK and PD properties. Future clinical development will require combination with either chemotherapy, or other immunotherapies such as antitumor vaccines or checkpoint inhibitors. Clinical trial information: NCT02829099.
Ramucirumab (Ram) and durvalumab (Durva) treatment of metastatic non-small cell lung cancer (NSCLC), gastric/gastroesophageal junction (G/GEJ) adenocarcinoma, and hepatocellular carcinoma (HCC) following progression on systemic treatment(s).
Authors: Bang Yung-Jue , Golan Talia , Lin Chia-Chi , Dahan Laetitia , Fu Siqing , Moreno Victor , Geva Ravit , Reck Martin , Wasserstrom Heather Ann , Mi Gu , Laing Naomi , Goff Laura Williams
Published: May 2019

2528

Background: A Phase 1b study (NCT02572687) was conducted to examine the combined effects of Ram (anti VEGFR2) and Durva (anti PD-L1). Methods: Patients (pts) with previously-treated, advanced NSCLC (Cohort [CH] A), G/GEJ adenocarcinoma (CH B), HCC (CH C), ECOG PS 0-1, and no prior Ram or IO therapy, received Ram (10 mg/kg) + Durva (1125 mg) Q3W (CH A) or Ram (8 mg/kg) + Durva (750 mg) Q2W (CH B, C). Primary objective was to assess safety; efficacy was also examined. PD-L1 expression of tumor cells (TC) +/- immune cells (IC) in pretreatment tumor biopsies were assessed using SP263 immunohistochemistry. “High” PD-L1 is ≥25% TC for NSCLC and ≥25% TC or IC for G/GEJ, HCC. Results: CH A, B and C enrolled pts with ECOG PS 1 (%) of 43, 66, 68; and average of 2, 2, 1 prior regimens, respectively. The most common grade 3/4 treatment-emergent adverse events (AE) are hypertension (HTN) (14.3, 17.2, 17.9%), anemia (3.6, 24.1, 21.4%), and fatigue (10.7, 10.3, 10.7%). Grade 3/4 AEs of special interest ( > 5% total pts) for Ram: HTN, bleeding events (3.6, 10.3, 10.7%), Venous thromboembolic events (0, 10.3, 7.1%); for Durva: increase in lipase (10.7, 3.4, 10.6%) and AST (3.6, 3.4, 17.9 %). Data from CH B,C suggest a trend toward increased efficacy in pts with high PD-L1 expressing tumors. Conclusions: Ram + Durva generated no unexpected toxicities and demonstrated antitumor activity. Results in pts with high PD-L1 HCC and G/GEJ cancer warrant further evaluation. Clinical trial information: NCT02572687. [Table: see text]
Clonal expansion of tumor infiltrating lymphocytes (TILs) in the peripheral blood of metastatic melanoma patients is significantly associated with response to CTLA4 blockade-based immunotherapy.
Authors: Khunger Arjun , Rytlewski Julie , Yusko Erik C. , Tarhini Ahmad A.
Published: May 2019

2541

Background: Patients with metastatic melanoma were treated on a clinical trial with tremelimumab and High Dose Interferon-Alfa (HDI) (Tarhini. J Clin Oncol. 2012). We previously reported that patients who achieved disease control and clinical response had significantly greater T-cell clonality (p = 0.0008) and T-cell fraction (p = 0.044) respectively in their pretreatment tumor biopsy samples (Tarhini. J Clin Oncol. 2017). In this study, we further characterize T-cell repertoire clonality and clonal expansion in the peripheral blood at different time points to evaluate the association between repertoire features and clinical response. Methods: Patients received tremelimumab 15 mg/kg I.V. every 12 weeks and HDI was given concurrently. Responses were assessed by RECIST as complete (CR) or partial (PR), stable disease (SD) or progression (PD). Peripheral blood mononuclear cells (PBMCs) from treated patients (N = 33) were obtained at baseline, day 29, and day 85 (following tremelimumab-HDI treatment); tumor samples at baseline were also obtained (N = 18). The T-cell receptor beta chain (TCRB) repertoire of PBMCs and tumor samples was immunosequenced using the immunoSEQ assay (Adaptive Biotechnologies), and repertoire clonality was assessed at baseline, day 29, and day 85. Differential abundance analysis was used to detect and quantify peripheral clonal expansion pre- versus post-treatment and identify the subset of peripheral clones also detected in the tumor repertoire. The Morisita Index of repertoire similarity was also calculated to compare global repertoire changes between pre- and post-treatment PBMC samples. Results: T-cell repertoire turnover, as measured by the Morisita Index, showed a trend towards responders (CR/PR) having greater turnover (lower Morisita Index) post-treatment than non-responders (SD/PD). Similarly, the total number of clones expanding in the peripheral repertoire varied over time within an individual (p = 0.034) but was not significantly affected by response to therapy (p = 0.275) or by on-treatment time point (p = 0.768). When the analysis was restricted to peripherally expanded clones that were also found in the tumor repertoire, responders had significantly more TILs expanded in the periphery at day 29 than non-responders (p = 0.036). Conclusions: Our analysis of the peripheral T-cell repertoire following treatment showed that detection of TILs in early peripheral clonal expansion correlates with response to therapy.
Molecular circulating tumor DNA response to identify long-term survival in patients receiving immunotherapy with initial radiologic stable disease.
Authors: Hellmann Matthew David , Zhang Qu , Abdullah Shaad Essa , Chaft Jamie E. , Segal Neil Howard , Gao Chen , Dennis Phillip A. , Higgs Brandon W.
Published: May 2019

2546

Background: Early on-treatment changes in ctDNA may identify responders to immunotherapy and complement radiologic assessment of benefit. Here we investigate how early changes in ctDNA associate with long-term survival following treatment with immunotherapy, and if differential patterns in molecular ctDNA response (MCR) among patients with radiologic stable disease (SD) at first on-treatment scan could identify patients deriving benefit from treatment. Methods: Paired pre- and on-treatment (week 6-8) plasma samples from 3 cohorts of patients treated with durvalumab (D) +/- tremelimumab (D+T) were evaluated (NCT01693562, NCT02087423, NCT02261220). CtDNA was profiled with the 73-gene Guardant 360 assay. Nonsynonymous variants were summarized per patient to calculate variant allelic frequency changes (dVAF) and on-treatment variant allele frequency (pVAF). A combination of dVAF and pVAF was used to define MCR. Results: The reduction of ctDNA (dVAF<0) and undetectable on-treatment ctDNA (pVAF=0) were each associated with improved OS and PFS. An optimal threshold for MCR was determined from one cohort, then applied to the other cohorts. MCR associated with significantly improved PFS and OS across all three cohorts (Table). MCR was then applied to a pooled subgroup of patients with initial radiologic SD from all three cohorts (n=78). Patients with radiologic SD and MCR were significantly more likely than those without MCR to achieve radiologic CR or PR (pooled Odds ratio 12.7, p<0.001), had improved PFS (stratified pooled HR 0.36, p<0.001), and improved OS (stratified pooled HR 0.38, p=0.005). Conclusions: MCR is an early on-treatment tool that may identify patients with improved long-term survival and patients with radiologic SD who derive clinical benefit from immunotherapy. MCR may be a supportive endpoint in prospective clinical trials. MCR and survival benefit. [Table: see text]
Community and academic partnerships: Moving a new generation of clinical trials in NCI Community Oncology Research Program (NCORP) into community oncology practices.
Authors: McCaskill-Stevens Worta J. , Geiger Ann M.
Published: May 2019

2551

Background: NCORP is a model program that bridges academic and community oncology practices and research. Over the past decade, community cancer investigators have adopted new technology, encountered new treatment sequalae, and faced rising cost of care with its financial toxicity imposed upon individuals seeking care. Opportunities are abundant for community investigators to assess feasibility and uptake of research advances into community practice settings, yet these opportunities are met with the challenges of dynamic changes in types of organizations delivering cancer care and diversity of populations within their catchment areas. Little information is shared about how and to what extent the health environment influences this partnership and the implementation of a broad cancer research portfolio. Methods: This abstract reports on the continued interest and participation of community oncologists in research which is demonstrated by 987 practices with over 4000 investigators in NCORP. Since 2014, over 30,000 individuals enrolled in symptom management, screening, surveillance, quality of life, and treatment trials. An additional 4500 patients and clinicians have enrolled in care delivery studies. Results: NCORP has been central in evaluating the most effective strategies for investigators to effectively communicate to patients the science of genomically-driven trials. It has also provided ways of bringing the pediatric and AYA patients access to the most up-to-date treatment strategies and new therapies in their community. This creates the least disruption on family structure/dynamics, diminished traveling requirements/costs, and reduced the financial burden. NCORP promotes involvement of treating oncologists in research activities. This also improves care for patients not enrolled in clinical trials. Therefore, NCORP serves as a laboratory to determine the most effective strategies for co-management of cancer patients and survivors. Conclusions: Several questions however remain to be addressed using this clinical trial model. These include: how to continue to reduce disparities in cancer care and clinical trial participation; and, what are the best strategies for fostering implementation of cancer care models in community practice.
Association between MDM2/MDM4 amplification and PD-1/PD-L1 inhibitors-related hyperprogressive disease: A pan-cancer analysis.
Authors: Ju Weiqiang , Chen Shiqing , Wang Guoqiang , Cai Shangli , Xiong Jianping , Xiang Xiaojun
Published: May 2019

2557

Background: Immune checkpoint inhibitors have demonstrated a clear survival benefit in various tumor types. However, accelerated disease progression, documented as hyperprogressive disease (HPD), was reported in a subset of patients treated with PD-1/PD-L1 inhibitors. Until now, the mechanisms underlying HPD have not been elucidated. Previous studies have demonstrated that MDM2/MDM4 amplification were associated with HPD. In the present study, we evaluated the relationship between MDM2/MDM4 amplification and HPD. Methods: We reviewed extensive clinical trials of PD-1/PD-L1 inhibitors in advanced solid tumor patients updated to January 2019, and estimated the incidence of HPD, which was defined as time-to-treatment failure (TTF) < 2 months, and > 50% increase in tumor burden compared with pre-immunotherapy imaging in this study. The proportions of MDM2/MDM4 amplification across different cancer types were obtained from The Cancer Genome Atlas (TCGA) and our own database respectively. Then we plotted the incidence of HPD and the corresponding proportion of MDM2/MDM4 amplification across various cancer types in TCGA. Results: Overall, 19 published clinical trials of 1318 patients treated with PD-1/PD-L1 inhibitors were included for analysis, covering 12 types of solid cancers. The incidences of HPD among these studies were ranging from 1.58% in renal clear cell carcinoma to 24.3% in sarcoma. Correspondingly, the proportions of MDM2/MDM4 amplification for these cancer types in TCGA were 0.74% in renal clear cell carcinoma to 20.38% in sarcoma. In our database, in total, 60 patients with MDM2/MDM4 amplification were identified in 2931 patients with the highest proportion of MDM2/MDM4 amplification in sarcoma (22 of 152, 14.5%). A significant correlation was detected between the incidence of HPD and the corresponding proportion of MDM2/MDM4 amplification in TCGA across various cancer types ( P < 0.001, R2 = 0.67). Conclusions: Our results suggest that MDM2/MDM4 amplification may be associated with rapid disease progression in patients receiving PD-1/PD-L1 inhibitors among various tumor types. The exact mechanisms underlying HPD are needed to be further evaluated.
Family history of cancer as surrogate predictor for immunotherapy with anti-PD-1/PD-L1 immune checkpoint inhibitors: The FAMI-L1 study.
Authors: Cortellini Alessio , Buti Sebastiano , Santini Daniele , Giusti Raffaele , Tiseo Marcello , Zoratto Federica , Marchetti Paolo , Bersanelli Melissa , De Galitiis Federica , Vitale Maria Giuseppa , Rastelli Francesca , Berardi Rossana , Tudini Marianna , Atzori Francesco , Iacono Daniela , Inno Alessandro , Bracarda Sergio , Natoli Clara , Ascierto Paolo Antonio , Ficorella Corrado
Published: May 2019

2559

Background: In the preliminary analysis of the FAMI-L1 study, we found a significant association between family history of cancer (FHC) and better clinical outcomes with anti-PD1/PD-L1 inhibitors. Methods: We retrospectively evaluated advanced cancer patients treated with single agents PD1/PD-L1 inhibitors. Patients were categorized as follow: FHC-high (in case of at least one cancer diagnoses in both straight and collateral family line), FHC-low (in case of a cancer diagnoses in only one family line) and FHC-negative. FHC was collected till the second degree of relatedness. Results: Between September 2013 and May 2018, 772 consecutive patients were evaluated. Median age was 68 years; male/female ratio was 521/251. Primary tumors were: NSCLC (58.3%), melanoma (22.1%), renal cell carcinoma (16.6%) and others (3%). 114 patients (14.9%) had ECOG-PS ≥ 2. 341 patients (44.3) were FHC-positive: 268 of them (34.75) were FHC-low while 74 (9.6%) were FHC-high. FHC-high patients had a significantly higher incidence of irAEs compared to FHC-negative (55.4% vs 35.6%; p = 0.0012) and to FHC-low (41.4%; p = 0.0323). No significant differences were found in terms of ORR among subgroups (data not shown). At median follow-up of 15.8 months, median PFS was 9.1 months (95%CI: 8.1-10.4; 452 events) and median OS was 19.7 months (95%CI: 15.7-24.4; 436 censored). No significant differences were found regarding PFS (data not shown). Median OS of FHC-high patients was 31.6 months (95%CI: 26.2-31.6; 50 censored patients), which was significantly longer than 18.2 months (95%CI: 14.7-21.3; 229 censored patients) of FHC-negative patients (HR = 0.60 [95%CI: 0.39–0.92), p = 0.0213). No significant differences in terms of OS were found between FHC-high/low patients (data not shown). After adjusting for primary tumor, sex, treatment-line, number of metastatic sites and ECOG-PS, FHC-high was confirmed an independent predictor of longer OS compared to FHC-negative (HR: 0.57 [95%CI: 0.37-0.88], p = 0.0098). Conclusions: FHC-high seems to be an independent predictor for longer OS in cancer patients treated with anti-PD-1/PD-L1. DNA damage and response (DDR) genes alterations may underlie that results.
Efficacy and a novel clinicopathologic-genomic nomogram of atezolizumab in advanced non-small cell lung cancer (POPLAR and OAK): A combined analysis of two multicenter, randomized, phase II/III trials.
Authors: Yu Yunfang , Chen Yongjian , Li Anlin , Ou Qiyun , Wang Ying , Ren Wei , Zhang Wenda , Tan Yujie , Yao Herui
Published: May 2019

2573

Background: Atezolizumab, a programmed death ligand 1 (PD-L1) inhibitor, prolonged overall survival (OS) compared with docetaxel among patients with previously treated advanced non–small-cell lung cancer (NSCLC) in two independent multicentre, randomized trials (POPLAR and OAK). We conducted a combined analysis of the two trials to evaluate its efficacy and genomic biomarkers, and to further developed a novel predictive clinicopathologic-genomic nomogram of immunotherapy in NSCLC. Methods: Patients (N = 1,137) with stage IIIB/IV NSCLC and disease progression after previously platinum-based chemotherapy were randomly assigned (1:1) to receive atezolizumab (1200 mg/kg every 3 weeks) or docetaxel (75 mg/m2 every 3 weeks). The primary endpoint was OS. We applied a two-stage meta-analysis of pooled individual patient data in the intention-to-treat population. In OAK trial, patients treated with atezolizumab were randomly assigned (1:1) to the training group or the validation group to develop a predictive clinicopathologic-genomic nomogram of immunotherapy. POPLAR and OAK were registered with ClinicalTrials.gov, numbers NCT02008227 and NCT01903993. Results: In the pooled analysis, the median overall survival was 13.49 months (95% confidence interval [CI], 11.95 to 15.22) with atezolizumab versus 9.66 months (95% CI, 8.73 to 10.70) with docetaxel. The risk of death was 28% lower with atezolizumab than with docetaxel (hazard ratio [HR], 0.72; 95% CI, 0.62 to 0.83; P < 0.001). The race, sex, tumor histology, eastern cooperative oncology group performance status, PD-L1 expression, and especially pretreatment mutation (TP53, DNMT3A and KEAP1) were significantly associated with OS, and were used for the development of the predictive nomogram. The clinical use of the nomogram showed a closer association with 3-year OS than the blood-based tumor mutational burden (bTMB) or PD-L1 expression alone (nomogram, AUC = 0.818; bTMB, AUC = 0.701; PD-L1, AUC = 0.526) among NSCLC patients who had received atezolizumab. The superior predictability of the nomogram was further confirmed in the validation and entire OAK cohorts. Conclusions: Among patients with advanced, previously treated NSCLC, OS was significantly better with atezolizumab than with docetaxel. Furthermore, we constructed a novel and powerful clinicopathologic-genomic nomogram for personalized immunotherapy options.
Effect of exonic microsatellite instability of B2M on the predictability of MSI/dMMR for immunotherapy.
Authors: Wei Jia , Zhong Fangfang , Wang Weifeng , Wu Nandie , Fu Yao , Mu Shuo , Wang Yue , Qian Xiaoping , Fan Xiangshan , Wang Kai , Liu Baorui
Published: May 2019

2576

Background: Microsatellite instability/mismatch repair deficiency (MSI/dMMR) has been approved as a biomarker for immune checkpoint inhibitor therapy (ICI) . However, the deficiency of mismatch repair system also caused wide-spreading insertion/deletion (indel) mutations in the exonic microsatellite sites of critical immunotherapy related genes such as β-2-macroglobulin (B2M) whose product is critical to antigen presentation. Cases of aquired resistance to ICI treatment caused by the inactivation of B2M have been reported. Therefore, we investigated the mutational profile of B2M across the MSI/dMMR high prevalent cancers such as colorectal cancer (CRC), gastric cancer (GC) and endometrial cancer (EC). Methods: FFPE tumor samples from 37 CRC, 46 GC and 25 EC patients with matched normal tissues were collected for next-generation sequencing (NGS)-based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, and gene rearrangement and tumor mutational burden were assessed. Immunohistochemistry (IHC) with antibody against B2M were performed on available samples to estimate the expression and localization of these proteins. Results: Exonic microsatellite sites of B2M gene have been found instable in 51% (19/37) of CRC, 22% (10/46) of GC and 8% (2/25) of EC. MSI caused small indels at B2M coding region leads to reading frame shift and the production of nonfunctional truncated proteins. Biallelic frameshift mutations, causing non-functional proteins, were found in 47% (9/19) of CRC and 30% (3/10) of GC patients carrying Indels in B2M gene. IHC assays showed the impaired expression of B2M proteins due to frameshift mutations. In addition, NGS test confirmed concurrent mutation in B2M for a MSI-H CRC patient with primary resistance to forth-line anti-PD1 treatment. Conclusions: The extensive mutations in the coding region of genes caused by the dMMR render the cancer cell sensitive to ICI. However, the concomitant variants in exonic microsatellite sites of B2M gene may compromise the predictability of MSI/dMMR as an ICI biomarker. Biallelic mutation of B2M may cause primary resistance to ICI while the mono-allelic mutation of B2M may gain acquired resistance. Therefore, B2M status could be considered when using MSI/dMMR as a biomarker for ICI.
MEDIPLEX: A phase 1 study of durvalumab (D) combined with pexidartinib (P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC).
Authors: Cassier Philippe Alexandre , Garin Gwenaelle , Eberst Lauriane , Delord Jean-Pierre , Chabaud Sylvie , Terret Catherine , Montane Laure , Bidaux Anne-Sophie , Laurent Séverine , Jaubert Lise , Ferlay Celine , Bernardin Mathilde , Tabone-Eglinger Séverine , Gilles-Afchain Laurence , Menetrier-Caux Christine , Caux Christophe , Treilleux Isabelle , Pérol David , Gomez-Roca Carlos Alberto
Published: May 2019

2579

Background: Targeting tumor associated macrophages is an emerging strategy to increase the responsiveness of PDAC and CRC to anti-PD(L)1. Pexidartinib (P) is an orally active, small-molecule kinase inhibitor that targets the colony-stimulating factor-1 receptor (CSF1R) on macrophages. Methods: Adult pts with advanced/ metastatic PDAC or CRC were treated with a fixed dose of D (1500mg q4w, IV) and ascending doses of P (400, 600, 800 and 1000mg/d, orally). Dose escalation was conducted according to a Likelihood Continual Reassessment Method with a 28-day window to evaluate dose-limiting toxicity (DLT), a stopping rule advised dose escalation termination in case of a high probability ( > 90%) for the next 6 pts to be assigned to the same dose. Following the determination of RP2D, 14 pts with PDAC and 14 pts with CRC who consented to serial tumor biopsies were enrolled in expansion cohorts to assess preliminary anti-tumor activity and biomarkers. Results: 19 pts (12M, 7F, median age, 56 y [range, 43-76y]) were enrolled in 4 dose escalation cohorts (P 400, 600 and 800mg/d: 3 pts each and P 1000mg/d: 10 pts). Pharmacokinetic analysis showed dose-dependent increase in the exposure of P from 400 to 1000 mg. Two DLTs (AST/ALT elevations including one with bilirubin increase) were seen at dose level P 1000mg/d. The most frequent ( > 2pts) related (to either D, P or both) AEs were: fatigue, maculopapular rash/pruritus/dry skin, hair color changes, anorexia, edema (periorbital, limbs or face), AST/ALT increases, bilirubin increases, nausea, vomiting and diarrhea. The most frequent (≥2pts) Grade ≥ 3 AEs related to P were: AST/ALT increase, ALP increase, neutrophil or white blood cell count decrease, and fatigue. Clinical benefit rate at 2 months was 21% (4 SD /19pts), 2 pts with MSI-H CRC had SD for more than 6 months including 1 pt still receiving single agent D after > 18 months. The RP2D for the combination was P 800mg/d + D 1500mg q4w. Enrolment in the expansion cohorts was completed in January 2019. Conclusions: Toxicity was consistent with the expected profiles of the individual drugs and no unexpected events were seen with the combination. Updated data will be presented at the meeting. Clinical trial information: NCT02777710.
Measuring the long-term “tail of curve” survival benefits in oncology trials: A comparison of the ASCO Value Framework and the ESMO Magnitude of Clinical Benefit Scale.
Authors: Everest Louis , Shah Monica , Chan Kelvin K.
Published: May 2019

2585

Background: Recently, anti-cancer agents have generated excitement due to their capacity to preserve long-term survival in some patients, represented by a “tail of the survival curve”. However, as traditional measures of clinical benefit may not accurately capture long-term survival, amendments to various valuation frameworks have been proposed to capture this benefit. The purpose of this study was to determine how frequently immune checkpoint inhibitor vs. non-immune checkpoint inhibitor anti-cancer agents, displayed trends of long-term survival, as defined by the American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), as well as to analyze the degree of agreement between ASCO and ESMO frameworks. Methods: Anti-cancer agents from phase II or III randomized controlled trials (RCTs) cited for clinical efficacy evidence in drug approval by the Food and Drug Administration (FDA) between January 2011 and March 2018 were identified. Data required for ASCO-VF and ESMO-MCBS were extracted. Difference in how often long-term survival bonuses were awarded were calculated in all RCTs, as well as immune checkpoint inhibitor and non-immune checkpoint inhibitor RCTs individually. Cohen’s Kappa statistic was calculated to evaluate agreement between ASCO-VF and ESMO-MCBS. Results: 100 RCTs were analyzed. RCTs were awarded ASCO-VF version 2 (v2) “tail of the curve” bonuses more often than ESMO-MCBS version 1.1 (v1.1) “immunotherapy-triggered” long-term plateau adjustments (45% vs. 2.6%). Comparing to non-immune checkpoint inhibitor RCTs, immune checkpoint inhibitor RCTs were not more likely to receive ASCO-VF v2 bonuses/ESMO-MCBS v1.1 adjustments (p = 0.32/ p = 0.40). Long-term survival agreement between the two frameworks was poor (kappa: 0.01; p = 0.50). Conclusions: The ASCO-VF v2 and ESMO-MCBS v1.1 may require additional refinement in order to accurately capture the benefit of long-term survival or immune checkpoint inhibitor and non-immune checkpoint inhibitor agents may not preserve substantially different long-term survival populations.
Genetic determinants of adverse events in cancer patients receiving immune checkpoint inhibitors.
Authors: Abdel-Wahab Noha , Yu Robert K , Diab Adi , Dadu Ramona , Shannon Vickie , Futreal Andrew , Criswell Lindsey A. , Shete Sanjay , Suarez-Almazor Maria E.
Published: May 2019

2586

Background: Immune checkpoint inhibitors (ICI) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAEs susceptibility as the phenotype of toxicity varies among patients (pts) and many pts do not develop toxicity despite continued inhibition. Methods: Genotyping was performed for 89 melanoma pts who received ICI using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data was extracted using PLINK (v1.90b3.34) and processed for quality control including on call rate (>99%), genotyping rate (>95%), minor allele frequency (no less than 5%), and Hardy-Weinberg Equilibrium (p<1x10-6). The pairwise genetic distance was calculated using identity-by-state (IBS matrix) implemented in the genome option of PLINK, and the population-structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p<1x10-3) and phenotype distribution for all pts, resulting in 7 structure groups. In the analytical stage, 602,463 variants in autosomal chromosomes were included for the association test. The test was performed using additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster. Results: 44 pts had arthritis, colitis, hypohysitis, thyroiditis, or multiple irAEs (cases), and 45 did not have irAEs after a minimum of one year of treatment (controls); median age was 64 (23-92) years; 71% were male. A total of 30 variants/single nucleotide polymorphisms (SNPs) had p-value smaller than 10^-5 level were identified. The top variants/SNPs are listed in table. Conclusions: Genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings, and to establish their potential functional relevance.[Table: see text]
Tumor mutation burden analysis in a 5,660 cancer patient cohort reveals cancer type-specific mechanisms for high mutation burden.
Authors: Jiao Xiaodong , Zhang Xiaochun , Qin Baodong , Liu Dong , Liu Liang , Ni Jianjiao , Zhou Ningyu , Chen Lingxiang , Zhu Liangjun , Qin Songbing , Zhou Jianya , Ying Shenpeng , Chen Xueqin , Li Aijun , Hou Ting , Zhang Tengfei , Chuai Shannon , Zang Yuan-Sheng
Published: May 2019

2589

Background: Tumor mutation burden (TMB), calculated by whole-exome sequencing (WES) or large NGS panels, has an important association with immunotherapy responses. Elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. Meanwhile, the landscape of TMB across different cancer types and its association with other molecular features have not been well investigated in large cohorts in China. Methods: Cancer patients whose fresh tissue (n = 1556), formalin-fixed, paraffin-embed (FFPE) specimen (n = 1794), and pleural fluid (n = 84) were profiled using 295- or 520-gene NGS panel. The association of the TMB status with a series of molecular features and biological pathways was interrogated using bootstrapping. Results: TMB, measured by 295- or 520-cancer-related gene panels, were correlated with WES TMB based on in silico simulation in the TCGA cohort. We compared the TMB landscape across 11 cancer type groups and found the highest average TMB in lung squamous cell carcinoma, whereas the lowest TMB was established in sarcoma. High microsatellite instability, DNA damage response deficiency, and homologous recombination repair deficiency indicated significantly higher TMB. The independent predictive power for TMB of twenty-six biological pathways was tested in 10 cancer groups. FoxO signaling pathway most commonly correlated with low-TMB; significant association was identified in four cancer groups. In contrast, no pathway was significantly correlated with high-TMB in more than two cancer groups. Overall, we discovered that the underlying pathways which may be the main drivers of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 14- and 22-gene signature for TMB prediction for LUAD and LUSC, respectively, with only 10 genes shared by both signatures, indicating a histology-specific mechanism for driving high-TMB in lung cancer. Conclusions: The findings extended the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types.
CD8+ T cells in tumor parenchyma and stroma by image analysis (IA) and gene expression profiling (GEP): Potential biomarkers for immuno-oncology (I-O) therapy.
Authors: Szabo Peter M , Lee George , Ely Scott , Baxi Vipul , Pokkalla Harsha , Elliott Hunter , Wang Dayong , Glass Benjamin , Kerner Jennifer K , Wapinski Ilan , Hedvat Cyrus , Locke Darren , Pandya Dimple , Adya Neeraj , Qi Zhenhao , Greenfield Alex , Edwards Robin , Montalto Michael
Published: May 2019

2594

Background: Distribution patterns of CD8+ T cells within the tumor microenvironment (TME) can be assessed by IA, which may reflect underlying tumor biology and serve as a potential biomarker to assess the utility of I-O therapy. These patterns are variable and may be classified as immune desert (minimal infiltrate), excluded (T cells confined to tumor stroma or to the invasive margin), or inflamed (T cells diffusely infiltrating tumor parenchyma and stroma). We hypothesized that association of a GEP signature with abundance of parenchymal and stromal T-cell infiltrates may identify biomarkers of response or resistance to I-O therapy. To test this, we applied an AI-powered IA platform to quantify CD8+ T cells by geographical location and used GEP to define both CD8 abundance and associated geographic localization to tumor parenchyma and stroma. Methods: We performed an analysis using a tumor inflammatory GEP assay and CD8 immunohistochemistry on procured specimens (335 melanoma, 391 SCCHN). Digitized slides were used to train a convolutional neural network to quantify the number of CD8+ T cells in stroma, tumor parenchyma, parenchyma-stromal interface, and invasive margin. Generalized constrained regression models were used to predict GEP signatures specifically for stromal and parenchymal CD8+ T cells. Results: Parenchymal and stromal GEP scores were highly concordant with CD8+ infiltrate geography (adj- r2: 0.67, 0.65, respectively; P ≤ 0.01). Little overlap existed between gene sets associated with parenchymal and stromal CD8 T-cell geographies. CSF1R and NECTIN2 gene expression was observed to correlate inversely with parenchymal localization and directly with stromal CD8+ T-cell abundance. Conclusions: GEP signatures can be identified that are concordant with various CD8+ T-cell localization patterns in melanoma and SCCHN, demonstrating that GEP-IA can be developed to identify the immune status of interest in the TME. The specific genes identified have potential to elucidate mechanisms of resistance and/or inform I-O targets that can be further evaluated in relation to clinical significance in future studies.