tbuckley/cabot-search huggingface dataset:
CD3<sup>+</sup> and CD8<sup>+</sup> tumor-infiltrating lymphocyte (TIL) densities to prognostically stratify DNA mismatch repair-deficient (dMMR) colon cancer patients (pts): NCCTG N0147 (Alliance).
Authors: Harry H. Yoon, Qian Shi, Erica N Heying, Andrea Muranyi, Faith Ough, Azita Djalilvand, June Clements, Rebecca Bowermaster, Wen-Wei Liu, Michael Barnes, Steven R. Alberts, Kandavel Shanmugam, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2018)

3598 Background: Colorectal cancers (CRC) with dMMR typically have abundant TILs indicating an enhanced host immune response. However, the prognostic impact of TILs identified by CD3+ and CD8+ T cells has not been adequately studied in dMMR tumors. While dMMR is considered a predictive biomarker for anti-PD-1 therapy in advanced CRC, ~60% of dMMR pts do not respond, which may be relevant in dMMR stage III where adjuvant PD-L1 blockade is being studied. We report the first evaluation of CD3+/CD8+ TILs with prognosis in dMMR tumors from a clinical trial cohort. Methods: CD3+ and CD8+ TILs at the invasive margin (IM) and central tumor (CT) were analyzed in 561 stage III colon cancers (dMMR n = 278; randomly selected pMMR n = 283) from a phase 3 trial of FOLFOX-based adjuvant therapy (N = 3270 [dMMR 376, pMMR 2894]). Median follow up was 6.3 y. Immunostaining was quantified by image analysis (0-100 scale). Associations with overall survival (OS) were evaluated by multivariable Cox regression. Results: Densities of CD3+ and CD8+ TILs were higher in dMMR vs pMMR tumors (P < .001), and were heterogeneous between pts in each MMR group. CD3+ IM was the strongest prognostic marker; the other markers (CD3+ CT, CD8+ IM, CD8+ CT), alone or combined, did not add further value. Among dMMR tumors, using an optimized cutpoint, 58% had low CD3+ IM, and these pts had significantly shorter OS v dMMR tumors with high CD3+ IM, independent of covariates. See Table for full results. OS of dMMR tumors with low CD3+ IM was comparable to the overall pMMR cohort (n = 2611; P = .8). Pts with high CD3+ IM pMMR tumors had an OS similar to TIL-unselected dMMR tumors (n = 376; P = .3). Conclusions: CD3+ IM TILs can prognostically stratify pts with dMMR stage III colon cancer for OS. These findings of heterogeneity within dMMR may have implications for immunotherapy responsiveness in dMMR tumors. CD3+ IM (cutpoint) n (%) HRadj Padj 5y OS rate dMMR Per 10-unit decrease 1.1 .015 High (≥ 49) 111 (42) Ref .026 84% Low (≤ 48) 167 (58) 2.1 70% pMMR Per 10-unit decrease 1.2 .009 High (≥ 21) 177 (63) Ref .073 83% Low (≤ 20) 106 (37) 1.7 73% Adjustments included T, N, grade, BRAF/KRAS, tumor side, age, smoking
A phase II study of study of bevacizumab (BEV) in combination with atezolizumab (ATEZO) in pts (pts) with untreated melanoma brain metastases (BEAT-MBM).
Authors: Gustavo Schvartsman, Isabella Claudia Glitza, Denai Milton, Rodabe Navroze Amaria, Patrick Hwu, Wen-Jen Hwu, Adi Diab, Michael K.K. Wong, Sapna Pradyuman Patel, Jeffrey Scott Wefel, Elizabeth M. Burton, Courtney Brown, Scott Eric Woodman, Ingrid M. Beosch, Caroline Chung, Michael A. Davies, Hussein Abdul-Hassan Tawbi
Journal: Journal of Clinical Oncology (2018)

TPS9598 Background: Immunotherapy (IO) has significantly improved survival for many pts with metastatic melanoma. However, the majority of trials excluded pts with MBM. Recently, combination of nivolumab and ipilimumab (IPI) showed objective response rate (ORR) of up to 55%, but pts with symptomatic disease still do poorly and usually are not candidates for IO due use of high dose steroids. Additionally, there is a concern for increased perilesional edema, which can lead to neurologic symptoms. BEV has widely been used as a “steroid-sparing agent” with remarkable success in controlling intracranial edema. Moreover, studies have implicated elevated angiogenic markers as predictors of poor outcome with IO by limiting effector T-cell trafficking and activity. Clinically, BEV has been shown to improve the outcome of IO and has indeed increased expression of favorable chemokines in the tumor microenvironment, improving ORR when added to IPI. Moreover, the combination of BEV and ATEZO, a PD-L1 inhibitor, produced remarkable responses in renal cell carcinoma. We therefore hypothesized that combining BEV and ATEZO will be more effective and have an improved toxicity profile in MBM. Methods: This phase II study will evaluate the intracranial safety and efficacy of BEV + ATEZO by ORR (iRANO criteria) in pts with untreated or progressive MBM who have not been exposed to PD-1/PD-L1 inhibitors. We will accrue 40 pts, divided in two cohorts: cohort A (25 asymptomatic pts); and cohort B (15 pts that are either mildly symptomatic, or asymptomatic, but requiring a low dose of systemic steroids (no higher than 4 mg/day of PO dexamethasone or equivalent). BEV will be given at 15 mg/kg and ATEZO at 1200 mg flat dose, both IV every 3 weeks until progression or death. Efficacy will be assessed by MRI of the brain and systemic imaging every 2 cycles. Continuous monitoring for toxicity and futility will be performed and assumes an ORR of 45% (96% power to detect a 25% difference from historical control of 20%). Effects of BEV + ATEZOL on correlative immune markers will be studied. This study is open for enrollment. Clinical trial information: NCT03175432.
Inter- and intra-patient heterogeneity of resistance mechanisms to the mutant EGFR selective inhibitor rociletinib.
Authors: Jacob J. Chabon, Andrew Simmons, Aaron M. Newman, Alexander F. Lovejoy, Mohammad S Esfahani, Henry Haringsma, David Matthew Kurtz, Henning Stehr, Florian Scherer, Kathleen A. Durkin, Gregory Alan Otterson, William T. Purcell, D. Ross Camidge, Jonathan Wade Goldman, Lecia V. Sequist, Zofia Piotrowska, Heather A. Wakelee, Joel W. Neal, Ash A. Alizadeh, Maximilian Diehn
Journal: Journal of Clinical Oncology (2016)

9000 Background: The third generation EGFR tyrosine kinase inhibitor (TKI) rociletinib has demonstrated activity in non-small cell lung cancer (NSCLC) patients (pts) who progressed on prior EGFR TKIs due to an acquired T790M resistance mutation. Additional work is needed to understand the mechanisms of resistance to rociletinib and other third generation EGFR TKIs. Methods: We employed circulating tumor DNA analysis using Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) to study putative mechanisms of innate and acquired resistance to rociletinib. CAPP-Seq was applied to a total of 115 serial plasma samples from T790M-positive NSCLC pts (n = 43) enrolled in the TIGER-X (n = 42) (NCT01526928) and TIGER-2 (n = 1) (NCT02147990) clinical trials. Results: Rociletinib resistance was diverse, with mutations and/or copy number gains affecting 9 genes involved in bypass pathway activation and tumor suppressor pathways. Multiple resistance mechanisms were observed in 23% of pts. Examples of emergent alterations included activating KRAS mutations in three pts, a novel tertiary mutation in EGFR (L798I) in one patient, and an EGFRC797S mutation in one patient. Increased MET copy number was the most frequently observed mechanism of resistance, occurring in 26% of cases. Pts with heterogeneity of resistance mechanisms at baseline (both T790M and increased MET copy number) displayed inferior responses and significantly shorter progression free survival (P < 0.05). In agreement with these clinical findings, erlotinib-resistant xenografts treated with rociletinib reproducibly developed MET amplification. Importantly, sensitivity to rociletinib could be reinstated by combined therapy with the METinhibitor crizotinib. Conclusions: We observed diverse and heterogeneous resistance mechanisms to rociletinib. The association of inferior outcomes with multiple resistance mechanisms at baseline emphasizes the clinical importance of tumor heterogeneity in these pts. Our results demonstrate that non-invasive profiling using ctDNA analysis can define patterns of resistance to targeted therapies and potentially allows for personalization of combination therapies to overcome resistance.
Identification of predictive and pharmacodynamic biomarkers associated with the first-in-class selective axl inhibitor bemcentinib across multiple phase II clinical trials.
Authors: Robert J Holt, David Micklem, Anthony Brown, Murray Yule, Sonja Loges, James Lorens
Journal: Journal of Clinical Oncology (2018)

2559 Background: AXL expression is strongly associated with immunosuppression and therapy resistance in a wide range of cancers. Bemcentinib is a first-in-class, orally bioavailable, selective AXL TKI which is being evaluated in solid tumours and myeloid malignancies in multiple Ph II clinical trials. Evidence of immune activation and reversal of therapy resistance upon treatment with bemcentinib has been observed in vivo as well as pts treated across the clinical programme. Here we report results of the accompanying biomarker research that utilises both liquid and tissue biopsies for gene expression, immunohistochemistry (IHC) and protein based analysis. Methods: Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) in a selection of pts pre-dose and at C2D1 across six clinical trials. Axl expression was measured in FFPE tissue samples together with an evaluation of distinct immune cell populations collected using multiplex IHC. Gene expression analysis was carried out by TaqMan qPCR. Results: Predictive and PD plasma biomarkers were identified in response to bemcentinib monotherapy in AML/MDS (NCT02488408), combination with pembrolizumab in NSCLC (NCT03184571), TNBC (NCT03184558) and melanoma (NCT02872259) as well as in NSCLC in combination with erlotinib (NCT02424617) and docetaxel (NCT02922777). Identified biomarkers include soluble AXL (sAXL) and other AXL regulated targets including angiogenin. A pharmacodynamic response of sAXL levels was observed after 1 cycle of treatment with bemcentinib which corresponded with the subset of pts that benefitted from treatment. Several biomarkers associated with treatment using bemcentinib + pembrolizumab across multiple different disease indications were also identified. AXL was detected by IHC in pt tumour tissue as well tumour associated immune cells. Conclusions: Results indicate the presence of predictive biomarkers which may be suitable for development into companion diagnostics to predict response to bemcentinib treatment. These biomarkers also confirm that bemcentinib has selective ‘on-target’ activity in a clinical setting.
Early clinical progression in patients with gynecologic malignancies receiving immunomodulatory antibody therapy.
Authors: Dmitriy Zamarin, Madhuri Martin, Nicholas Zecca, Alexia Iasonos, Qin Zhou, Carol Aghajanian, Paul Sabbatini
Journal: Journal of Clinical Oncology (2017)

e17087 Background: The success of immunomodulatory antibodies have led to their increasing investigation in GYN cancers. Many of these patients, however, discontinue the drugs early in treatment due to symptomatic progression, making it challenging to assess clinical benefit and late responses associated with these agents. Here, we describe the clinical characteristics underlying early progression requiring immunotherapy discontinuation in order to better guide patient selection for such trials. Methods: A retrospective analysis was performed on all GYN cancer patients treated with immunomodulatory antibodies at MSKCC between 1/2013 and 6/2016. Patients were defined as early progressors if they had clinical/radiographic disease progression before 12 weeks which required therapy discontinuation. Logistic regression was applied to model the relationship between baseline clinical and radiographic characteristics and early progression. P&lt;0.05 was considered to be statistically significant. Results: A total of 105 patients met the inclusion criteria, with 74 (71%) with ovarian cancer. Therapeutic targets included CTLA-4 (3%), and PD-1/PD-L1 alone and in combination with other targets (97%). Of these, 55 (52%) met the criteria for early progression requiring therapy discontinuation (median therapy duration 7 weeks, range 1.6-12.1). There was an increased risk for early progression in patients with pre-treatment ascites (p=0.005, OR 6.4, 95% CI 1.7-23.7), and with baseline bulky disease, defined by at least one tumor measuring ≥ 5cm, compared to patients with tumors &lt;5cm (p=0.001, OR 4.1, 95% CI 1.7-9.9). Clinical symptoms/deterioration were the reason for early discontinuation in 35 (64%) of the patients, with symptomatic ascites and abdominal pain as the most common complaints. Conclusions: Symptomatic clinical progression of peritoneal disease leading to early discontinuation of immunomodulatory antibody therapy is common in patients with GYN cancers and is associated with increased pre-treatment disease volume. The extent of peritoneal disease should be taken into strong consideration when selecting GYN cancer patients for trials with immunomodulatory antibody therapy.
Single-cell transcriptomics reveal that PD-1 mediates immune tolerance by regulating proliferation of regulatory T cells
Authors: Cherry S. Leung, Kevin Y. Yang, Xisheng Li, Vicken W. Chan, Manching Ku, Herman Waldmann, Shohei Hori, Jason C. H. Tsang, Yuk Ming Dennis Lo, Kathy O. Lui
Journal: Genome Medicine (2018)

We have previously reported an antigen-specific protocol to induce transplant tolerance and linked suppression to human embryonic stem cell (hESC)-derived tissues in immunocompetent mice through coreceptor and costimulation blockade. However, the exact mechanisms of acquired immune tolerance in this model have remained unclear. We utilize the NOD.Foxp3hCD2 reporter mouse line and an ablative anti-hCD2 antibody to ask if CD4+FOXP3+ regulatory T cells (Treg) are required for coreceptor and costimulation blockade-induced immune tolerance. We also perform genome-wide single-cell RNA-sequencing to interrogate Treg during immune rejection and tolerance and to indicate possible mechanisms involved in sustaining Treg function. We show that Treg are indispensable for tolerance induced by coreceptor and costimulation blockade as depletion of which with an anti-hCD2 antibody resulted in rejection of hESC-derived pancreatic islets in NOD.Foxp3hCD2 mice. Single-cell transcriptomic profiling of 12,964 intragraft CD4+ T cells derived from rejecting and tolerated grafts reveals that Treg are heterogeneous and functionally distinct in the two outcomes of transplant rejection and tolerance. Treg appear to mainly promote chemotactic and ubiquitin-dependent protein catabolism during transplant rejection while seeming to harness proliferative and immunosuppressive function during tolerance. We also demonstrate that this form of acquired transplant tolerance is associated with increased proliferation and PD-1 expression by Treg. Blocking PD-1 signaling with a neutralizing anti-PD-1 antibody leads to reduced Treg proliferation and graft rejection. Our results suggest that short-term coreceptor and costimulation blockade mediates immune tolerance to hESC-derived pancreatic islets by promoting Treg proliferation through engagement of PD-1. Our findings could give new insights into clinical development of hESC-derived pancreatic tissues, combined with immunotherapies that expand intragraft Treg, as a potentially sustainable alternative treatment for T1D.
Bayesian AI to delineate molecular signatures of patient susceptibility to potential hematologic events in a phase I study of BPM31510 (ubidecarenone) in solid tumors.
Authors: Rangaprasad Sarangarajan, Vivek Subbiah, David S. Hong, Michael Kiebish, Vivek Vishnudas, Eric M Grund, Gregory M Miller, Leonardo O Rodrigues, Hedy Dion, Janice Stevens, Viacheslav R Akmaev, Niven R. Narain
Journal: Journal of Clinical Oncology (2017)

e14042 Background: BPM 31510 is a ubidecarenone containing nanodispersion elicits anticancer effect by switching cancer cells energy generation from glycolysis to mitochondrial OXPHOS; i.e. reverses Warburg effect. This Phase 1 study is evaluating safety of 144-hour infusion of BPM 31510 as a single agent and in combination with 3 standard chemotherapy regimens. The molecular adaptive study design enabled longitudinal multi-omic molecular profiling to delineate personalized cause-and-effect networks relating patient biology to clinical outcomes using unbiased Bayesian statistics based bAIcis Artificial Intelligence (AI) technology Methods: Eligible pts (aged ≥ 18 y) were relapsed/refractory to standard therapy. The monotherapy arm received IV BPM31510 for 144-hour infusion in 28d cycles, and combination arms (gemcitabine, 5-FU or docetaxel) were primed with BPM 31510 for 3 wks followed by weekly dosing in a 6wk cycle. Doses were escalated in a 3+3 schema. Endpoints were safety, PK and multi-omics analysis. Clinical information was processed and integrated with multi-omic molecular data (metabolomics, lipidomics and proteomics), utilized bAIcis to learn relationships and extract actionable information from pt records, molecular features and corresponding clinical response. Results: As of 10 Dec 2016, 97 pts have been enrolled. Hematologically-related DLTs were reported at 171mg/kg in monotherapy and 137mg/kg in the BPM31510+gemcitabine arm (maximum administered dose). The bAIcis-generated set of predictors defining coagulation-related events in the clinical trial population include proteins, lipids, and metabolites, the levels of which can potentially predict undesirable events prior to and 24h after the 1 st treatment with BPM 31510. Conclusions: BPM31510 is well tolerated as a monotherapy and in combination with chemotherapeutic agents. Molecular signatures of susceptibility have been identified through use of multi-omic based AI analysis. Molecular signatures predictive of coagulation-related events will be assessed in Phase 2 and 3 trials to guide the development plan for BPM 31510 as anticancer agent. Clinical trial information: NCT01957735.
Pharmacodynamics (PD) and genomic profiling of pts treated with cabiralizumab (cabira) + nivolumab (NIVO) provide evidence of on-target tumor immune modulations and support future clinical applications.
Authors: Michael Carleton, Janine Powers, Penny Phillips, Muhammad Shaalan Beg, James J. Lee, Osama E. Rahma, Sarina Anne Piha-Paul, Ernestine Lee, Kevin Hestir, Ke Xu, Dimple Pandya, Sandeep P. Inamdar, Serena K Perna, Shih-Min A. Huang, Zev A. Wainberg
Journal: Journal of Clinical Oncology (2018)

3020 Background: Colony stimulating factor 1 receptor (CSF-1R) signaling supports recruitment, development, and maintenance of immune suppressive macrophages within the tumor. Combining anti–CSF-1R with anti‒PD-1 showed enhanced efficacy in preclinical models. Cabira, a humanized IgG4 monoclonal antibody, disrupts CSF-1R binding to ligands CSF-1 and IL-34, thus blocking receptor activation. We report immunohistochemistry (IHC) and transcriptomic evidence of on-target PD effects of cabira + NIVO in treated pts, as well as the first insight into genotypic characteristics of pancreatic tumors exhibiting durable PRs with cabira + NIVO (Wainberg et al. J Immunother Cancer 2017;5(suppl 2) [abst O42]). Methods: PD activity of cabira + NIVO in pts with advanced tumors treated in a ph 1a/b trial (NCT02526017) was evaluated using peripheral and tumor biomarkers. Results: Cabira + NIVO induced increases in serum CSF-1 and decreases in peripheral nonclassical monocytes sustained during the 2-week dose interval. IHC analysis of pre- and on-treatment biopsies across tumor types showed increases in CD8 T-cell infiltrates and decreases in macrophage markers CSF-1R and CD163. Transcriptomes of paired biopsies showed increased CD8 and cytolytic gene signatures with concurrent increased expression of M1 macrophage-associated genes, supporting blockade of CSF-1R–driven M2 responses. Genomic analyses demonstrated 91 of 94 pts with low tumor mutation burden (TMB) below 10 mutations/megabase with only 1 microsatellite instability tumor identified. Responses were observed across tumor types. Of note, in the 4 PRs observed in pts with pancreatic cancer, all were microsatellite stable (MSS) and low TMB. Conclusions: Orthogonal IHC and transcriptome-wide analyses demonstrated cabira-mediated CSF-1R blockade in the periphery and tumor microenvironment in pts with advanced cancer. Ongoing analyses include identification of transcriptomic signatures associated with response. These data support further clinical development of cabira + NIVO in multiple indications, including MSS pancreatic cancer (NCT03336216). Clinical trial information: NCT02526017.
Phase III trial of s-1 plus oxaliplatin (SOX) vs s-1 plus cisplatin (SP) combination chemotherapy for first-line treatment of advanced gastric cancer (AGC): SOPP study.
Authors: Min-Hee Ryu, Young Iee Park, Ik-Joo Chung, Keun-Wook Lee, Ho-Suk Oh, Kyung Hee Lee, Hye Sook Han, Bong-Gun Seo, Jae-Cheol Jo, Hyo Rak Lee, Sook Ryun Park, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2016)

4015 Background: S-1 plus cisplatin (SP) is one of the standard first-line chemotherapies for AGC in the East Asia. Oxaliplatin is generally less toxic and more convenient than cisplatin. This study compared the safety and efficacy of S-1 plus oxaliplatin (SOX) with those of SP. Methods: This SOPP study was a multi-center, randomized, open-label, phase III study to evaluate whether SOX was non-inferior / superior to SP in terms of progression-free survival (PFS) according to RECIST v1.1. Patients (pts) with metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma and no prior chemotherapy were randomized 1:1 to receive either SOX (S-1 80 mg/m2/day on D1-14, oxaliplatin 130 mg/m2 on D1, every 3 weeks) or SP (S-1 80 mg/m2/day on D1-14, cisplatin 60mg/m2 on D1, every 3 weeks) until disease progression or unacceptable toxicities. Results: Between October 2012 and October 2014, a total of 338 pts were randomized from 10 sites in Korea. The median age was 56 years (range, 26-80). 98% of pts had ECOG performance status 0-1. 51% of pts had measurable lesions. With a median follow-up of 15.6 months (range, 0.1-33.3) in surviving pts, SOX was significantly non-inferior but not superior to SP in PFS (median 5.6 months vs. 5.7 months; HR 0.85, 95% CI 0.67-1.07, p = 0.169). In pts with measurable disease, overall response rates (ORR) were similar between SOX and SP (58% vs. 60%, p = 0.7). Overall survival (OS) of both groups was not different, either (median 12.9 vs. 11.4 months; HR 0.86, 95% CI 0.66-1.11, p = 0.242). Treatment was generally well tolerated in both arms. While grade 3/4 neutropenia and febrile neutropenia were more common in SP, grade 3/4 peripheral neuropathy and thrombocytopenia were more common in SOX. Conclusions: SOX was non-inferior to SP in terms of PFS, ORR, and OS. The two regimens were well tolerated with different toxicity profiles. SOX regimen can be also recommended as a first-line treatment of AGC. Clinical trial information: NCT01671449.