Browsing Over 191 Presentations
PET imaging of monocytes and macrophages
- Tony Lahoutte
- Tony Lahoutte
The immunogenic effects of VEGF targeted therapy: Fact or fiction?
- Thomas Powles
- Thomas Powles
Invited Discussant LBA1_PR
- Solange Peters
- Naiyer Rizvi
- Solange Peters
- Naiyer Rizvi
Primary PFS and safety analyses of a randomized Phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150)
- Martin Reck
- Martin Reck
- Mark A. Socinski
- Federico Cappuzzo
- Francisco Orlandi
- Daniil Stroyakovskii
- Naoyuki Nogami
- Delvys Rodríguez-Abreu
- Denis Moro-Sibilot
- Christian A. Thomas
- Fabrice Barlesi
- Gene Finley
- Claudia Kelsch
- Anthony Lee
- Shelley Coleman
- Yijing Shen
- Marcin Kowanetz
- Ariel Lopez-Chavez
- Alan Sandler
- Robert Jotte
Abstract
Background
Atezolizumab (atezo; anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1, restoring anti-cancer immunity. Bev may further enhance atezo efficacy by inhibiting VEGF immunosuppression and promoting T-cell tumour infiltration. IMpower150 evaluates the addition of atezo to carboplatin (C) + paclitaxel (P) ± bevacizumab (bev) in chemo-naive patients (pts) with non-squamous (NSQ) mNSCLC.
Methods
1202 pts received atezo 1200 mg + C AUC 6 + P 200 mg/m2 (Arm A) or atezo + bev 15 mg/kg + C + P (Arm B) vs bev + C + P (Arm C) IV q3w for 4 or 6 cycles per investigator (INV) discretion, then maintenance atezo, atezo + bev or bev, respectively. Co-primary endpoints assessed at this data cutoff (15 Sep 2017; minimum follow up, 9.5 mo) were INV-assessed PFS in the ITT-WT (EGFR or ALK negative) population and in WT pts with expression of a tumour T-effector gene signature (Teff-WT; centrally assessed), and OS in the ITT-WT population, for the Arm B vs Arm C comparison. Due to pre-specified statistical testing hierarchy, Arm A vs Arm C has not been formally tested yet.
Results
356 pts in Arm B and 336 pts in Arm C were enrolled in the ITT-WT. Median age was 63 y; 60% were previous smokers (both arms). 61% and 62% were male, and 39% and 43% had ECOG PS 0 in Arms B and C, respectively. The HRs for INV-assessed PFS in Arm B vs C were 0.62 (95% CI: 0.52, 0.74; P < 0.0001) in the ITT-WT and 0.51 (0.38, 0.68; P < 0.0001) in the Teff-WT populations. Median PFS in Arm B vs C was 8.3 mo vs 6.8 mo and 11.3 mo vs 6.8 mo in the ITT-WT and Teff-WT populations, respectively. PFS benefit was seen regardless of PD-L1 IHC status, including PD-L1–negative pts (TC0/IC0; HR, 0.77 [95% CI: 0.61, 0.99]). Landmark PFS and ORR are shown (Table). Arm B had a comparable safety profile to Arm C; treatment-related serious AEs were 25% vs 19%, respectively.
Conclusions
IMpower150 is the first Ph 3 study to show a statistically significant and clinically meaningful PFS benefit with atezo + bev + chemo vs bev + chemo in pts with 1L NSQ mNSCLC.
Table. IMpower150 Primary PFS Analysis, landmark PFS and ORR | ||
Arm C | Arm B | |
ITT-WT populationa | n = 336 | n = 356 |
Median PFS (95% CI), mo | 6.8 (6.0, 7.1) | 8.3 (7.7, 9.8) |
HR (95% CI; P value) | 0.62 (0.52, 0.74; P < 0.0001) | |
ITT-WT landmark PFS (95% CI), % | ||
6-month | 56% (51, 62) | 67% (62, 72) |
12-month | 18% (13, 23) | 37% (31, 42) |
ORRb,c (95% CI), % | 48% (43, 54) | 64% (58, 68) |
Teff-WT populationa | n = 129 | n = 155 |
Median PFS (95% CI), mo | 6.8 (5.9, 7.4) | 11.3 (9.1, 13.0) |
HR (95% CI; P value) | 0.51 (0.38, 0.68; P < 0.0001) | |
Teff-WT landmark PFS (95% CI), % | ||
6-month | 57% (48, 66) | 72% (65, 79) |
12-month | 18% (10, 25) | 46% (38, 54) |
ORRb,d (95% CI), % | 54% (44, 62) | 69% (61, 76) |
DOR, duration of response; HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival; Teff, T-effector; WT, wild-type. |
Clinical trial identification
NCT02366143
Invited Discussant 6O, 7O and 8O_PR
- Ignacio Melero
- Ignacio Melero
Invited Discussant 3O, 4O and 5O_PR
- Heinz Zwierzina
- Heinz Zwierzina
Efficacy of PEGylated human IL-10 (AM0010) in combination with anti-PD-1 blockade in patients (pts) with metastatic renal cell carcinoma (mRCC): A phase 1b trial
- Aung Naing
- Aung Naing
- Jeffrey Infante
- Deborah Wong
- W. Michael Korn
- Raid Aljumaily
- Kyri Papadopoulos
- Karen Autio
- Shubham Pant
- Todd Bauer
- Alexandra Drakaki
- Naval Daver
- Annie Hung
- Peter Van Vlasselaer
- Martin Oft
- Nizar Tannir
Abstract
Background
IL-10 is anti-inflammatory and stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are expressed on activated and exhausted CD8 T cells, providing a rationale for combining AM0010 and an anti-PD1 antibody. 4 of 16 heavily pre-treated pts with poor- or intermediate-risk mRCC, achieved a PR with AM0010 alone.
Methods
38 pts with metastatic RCC were enrolled from 2/20/2015 to 11/18/16 on AM0010 (10 or 20 ug/kg daily SC) and nivolumab (n = 29; 3mg/kg, q2wk IV) or pembrolizumab (n = 9; 2mg/kg, q3wk IV). Three had favorable and 30 had intermediate or poor-risk by IMDC (5 data not available). Pts had a median of 1 prior therapy (range: 1-3), and at least one VEGFR-TKI. One patient with prior AM0010 was included the safety population only. Tumor responses were assessed by irRC. Serum cytokines, blood derived T cells, clonal identity of peripheral T cells, and tumor DNA sequence and mRNA profiling were assayed.
Results
AMO010 plus nivolumab (nivo) or pembrolizumab (pembro) was well tolerated. TrAEs were reversible and transient. G3/4 TrAE in patients on AM0010 and nivo or pembro included anemia (10), thrombocytopenia (7), and hypertriglyceridemia (6). Two pts had a reversible cytokine release syndrome with splenomegaly and increased immune mediated red blood cell phagocytosis (HLH) most likely precipitated by T-cell activation, as both pts had a PRs. Patients treated with 10ug/kg AM0010 and nivo or pembro did not have G3/4 anemia or thrombocytopenia. As of August 11 2017, PRs were observed in 14 of 34 evaluable pts (41%). An additional 13 pts had stable disease (38%), 8 of those had a tumor reduction of more than 30% following irRC (in progress). Median PFS and median OS have not been reached, at median FU of 13.5 months (range: 0.5-29.83) for the nivolumab arm. mRNA analysis was used to distinguish patients with CR/PR/SD from progressive disease. Responding patients had a higher degree of CD8+ T cell invigoration.
Conclusions
The combination of AM0010 with nivo or pembro is well-tolerated in mRCC pts; the recommended phase 2 dose is 10ug/kg. The observed efficacy is very promising and further studies of AM0010 and nivo or pembro in mRCC are in preparation.
Clinical trial identification
NCT02009449
Legal entity responsible for the study
ARMO BioSciences
Funding
ARMO BioSciences
Disclosure
A. Hung, P. Van Vlasselaer: Employee of ARMO BioSciences. M. Oft: Founder and employee of ARMO BioSciences. All other authors have declared no conflicts of interest.
Phase 1 study of E7046, a PGE2 receptor EP-4 inhibitor that targets immunosuppressive myeloid cells in the tumor microenvironment (TME)
- Aparna Parikh
- David Hong
- Andrea Varga
- Aparna Parikh
- Geoffrey Shapiro
- Larisa Reyderman
- Min Ren
- Satish Dayal
- Terri Binder
- Chean Eng Ooi
- Özlem Ataman
- Aurélien Marabelle
Abstract
Background
E7046 is a selective small molecule antagonist of the prostaglandin E2 receptor-type-4 that inhibits the differentiation of monocytic myeloid lineage cells towards a pro-tumorigenic phenotype in the TME. This is a first-in-human study of single agent E7046.
Methods
Key eligibility criteria: patients (pts) ≥18 years with selected advanced cancers with high levels of myeloid infiltrate. The dose-escalation phase consisted of 6-pt cohorts of 125, 250, 500, and 750 mg (once-daily, oral, 21-day cycle) doses of E7046. Primary objectives were safety/tolerability, maximum tolerated dose (MTD) and/or RP2D. Secondary objectives included PK and initial anti-tumor activity; exploratory objectives included PD assessments on immune cells in tumor infiltrate and in peripheral blood and metabolic response by 18FDG-PET.
Results
30 pts received E7046 (median age 58 yrs [24-78]; 2-7 lines of prior therapy). Most common tumor types were colorectal cancer (40%), pancreatic cancer (20%), and SCCHN (13%). No DLTs were observed and the MTD was not reached. The most frequent drug-related adverse events (AEs) were diarrhea (20%), decreased appetite, fatigue and nausea (13% each). Drug-related AEs of Gr 3/4 occurred in 4 pts (diarrhea, anaphylactic reaction, hypersensitivity, hyperuricemia, rash, generalized rash). 2 pts had drug-related serious AEs (rash, allergic reaction, fever in 1 pt; hyperuricemia, acute renal failure [Gr 2] in 1 pt). 3 pts discontinued treatment due to AEs (bowel obstruction, allergic reaction, abdominal pain). There were no drug-related deaths. E7046 exposure was dose proportional up to 500 mg with no incremental increase in exposure at 750 mg. E7046 was extensively metabolized, elimination half-life was ∼12hr and accumulation on multiple dosing was ∼2-fold. 2 pts are ongoing and preliminary efficacy showed no objective responses, 4 pts with durable SD or clinically stable (>4 mo) and 4 pts with 18FDG-PET metabolic responses.
Conclusions
Single-agent E7046 was tolerated with no MTD reached in heavily pretreated pts with myeloid-rich tumors. PD analysis of immune cell modulation to help determine the RP2D will be presented at the meeting.
Clinical trial identification
NCT02540291
Legal entity responsible for the study
Eisai Inc.
Funding
Eisai Inc.
Disclosure
D. Hong: Research/Grant Funding: Bayer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichi-Sanko, Eisai; Travel, accommodations, expenses: MiRNA, LOXO; Consulting or Advisory Role: Bayer, Baxter, Guidepoint Global; Other ownership interests: Oncoreseponse (founder). A. Parikh: Personal fees from Roche, outside the submitted work. G. Shapiro: Consulting: Pfizer, Lilly, G1 Therapeutics, Vertex, Roche; Research funding: Lilly. L. Reyderman, M. Ren, T. Binder, C.E. Ooi: Employee of Eisai Inc. S. Dayal: Employee of Eisai Ltd. Ö. Ataman: Former employee of Eisai Ltd. at time of study. A. Marabelle: Received clinical trial funding from Eisai; Received consulting fees from Eisai and Roche; Received funding for anti-CSF1R clinical trial from Roche. All other authors have declared no conflicts of interest.
A Phase 1b/2 Study of Omaveloxolone in Combination with Checkpoint Inhibitors in Patients with Unresectable or Metastatic Melanoma
- Sapna P. Patel
- Sapna P. Patel
- F. Stephen Hodi
- Dmitry Gabrilovich
- Melanie Chin
- Geoff Gibney
- Angie Goldsberry
- Rene Gonzalez
- Jason Hurt
- Joseph Markowitz
- Eric Whitman
- Colin Meyer
- April Salama
Abstract
Background
Omaveloxolone (Omav) reduces production of reactive oxygen and nitrogen species by myeloid derived suppressor cells (MDSCs) and restores immune surveillance in preclinical cancer models. Administration of Omav with checkpoint inhibitors (CI) may enhance the anti-tumor immune response of immunotherapies. A Phase 1b/2 study was designed to evaluate the safety and efficacy of Omav in combination with ipilimumab (Ipi) or nivolumab (Nivo) for treatment of patients with unresectable or metastatic melanoma. Data from the ongoing Phase 1b study are reported.
Methods
Patients with or without prior exposure to CI, and with >5% of tumor cells from a screening biopsy positive for inducible nitric oxide synthase (iNOS) were enrolled. Serial biopsies were also collected at Weeks 2 and 13. Omav monotherapy (5, 10, 20, 100, or 150 mg PO QD) was dosed continuously starting one week prior to CI initiation (Ipi x 4 doses or Nivo q 2 weeks). Primary objectives were safety, MTD, and ORR measured via RECIST v1.1.
Results
At data cutoff, 39 patients were enrolled (Omav + Ipi: n=12; Omav + Nivo: n=27) with median treatment duration of 13 weeks. Of 30 patients with evaluable tumor restaging, 7/30 (23%) of patients were CI-naïve, while 23/30 (77%) of patients were refractory to prior CI therapy. The ORR (confirmed + unconfirmed) observed in all evaluable patients was 8/30 (27%, 6 partial response (PR) and 2 complete response (CR)) and 4/7 (57%) in CI-naïve patients, including 1 CR. 3/18 (17%) patients treated with Omav + Nivo who were refractory to prior CI therapies had objective responses including 1 CR. Omav was associated with decreases in tumor iNOS, PD-L1, and IDO-1 expression. The MTD for Omav has not been established since no dose-limiting toxicities were observed. No serious AEs considered related to Omav have been reported to date. Commonly reported treatment-related adverse events included fatigue, nausea, pruritus, transaminase increases and decreased appetite.
Conclusions
Omav was well tolerated at doses up to 150 mg in combination with CI and initial efficacy data suggest that Omav may overcome CI resistance. The Phase 2 portion of the trial will study the effects of Omav with Nivo in patients refractory to prior anti-PD-1/PD-L1 therapies.
Clinical trial identification
NCT02259231
IVAC MUTANOME: A first-in-human phase I clinical trial targeting individual mutant neoantigens for the treatment of melanoma
- Matthias Miller
- Matthias Miller
- Ugur Sahin
- Evelyna Derhovanessian
- Björn-Philipp Kloke
- Petra Simon
- Valesca Bukur
- Christian Albrecht
- Anna Paruzynski
- Martin Löwer
- Andreas Kuhn
- Katharina Schreeb
- Sebastian Attig
- Alexandra Kemmer Brueck
- Stefanie Bolte
- Stephan Grabbe
- Christoph Höller
- Jochen Utikal
- Christoph Huber
- Carmen Loquai
- Özlem Türeci
Abstract
Background
The genome of cancer cells is inherently instable promoting multiple genomic alterations and epigenetic changes. This process leads to a unique molecular profile of every given tumor. Recently, a series of independent reports revealed that neo-antigen specific T-cell responses are seminal for the clinical efficacy of immune checkpoint inhibitors. However, less than 1% of mutations appear to raise spontaneously occurring T-cell response in the tumor-bearing patient. Accordingly, only patients with a high burden of mutations profit from currently approved therapies. To overcome this restriction, the IVAC® MUTANOME, a highly potent personalized neo-antigen-encoding RNA vaccine approach, harnesses the individual patient’s mutation profile. To this aim, the individual mutation repertoire is identified by next-generation-sequencing and 10 potentially immunogenic mutated sequences per patient are selected. These are incorporated into a poly-epitopic RNA vaccine (IVAC MUTANOME®) that is tailored to activate and expand the individual patient’s T cells against the unique mutation signature.
Methods
A phase I first-in-human trial has been initiated in 2013 in patients with stage III and IV malignant melanoma (NCT02035956) to test this fully personalized RNA vaccine concept. The objective of this clinical trial is to study the feasibility, safety, tolerability, immunogenicity and the potential anti-tumoral activity of the IVAC® MUTANOME approach.
Results
As of November 2016, 13 patients were evaluable for the assessment of the safety profile and the induction of antigen-specific immune responses. Notably, in each and every patient a strong poly-neo-epitopic immune response against vaccine antigens was detected. Overall, 60% of the 125 selected neo-epitopes elicited a T-cell response. Simultaneously, no severe adverse drug reactions were reported and indications for clinical activity were observed.
Conclusions
Vaccination with IVAC® MUTANOME was very well tolerated. A high pharmacological activity of the vaccine was observed in all enrolled patients encouraging further clinical development.
Clinical trial identification
NCT02035956; First Posted: January 14, 2014
Legal entity responsible for the study
Biontech RNA Pharmaceuticals GmbH
Funding
CI3 cluster program of the German Federal Ministry of Education and Research (BMBF).
Disclosure
M. Miller, K. Schreeb, S. Bolte: Employee of BioNTech AG. U. Sahin: Stock owner and management board member of BioNTech group; Co-founder and CEO BioNTech AG, Mainz. Head of the Scientific Advisory Board of Ganymed Pharmaceuticals AG. E. Derhovanessian, B-P. Kloke, P. Simon, V. Bukur, C. Albrecht, A. Kuhn, A. Kemmer Brueck, A. Paruzynski: Employee of the BioNTech group. S. Grabbe: AbbVie: Advisory Board, Reimbursement of travel costs. BMS: Advisory Board, Honorarium (oral presentation), Reimbursement of travel costs. MSD: Advisory Board, Honorarium (oral presentation), Reimbursement of travel costs. OnkoZert: Honorarium (Auditor), Reimbursement of travel costs. Roche: Advisory Board, Honorarium (oral presentation), Reimbursement of travel costs. Sanofi-Pasteur-MSD: Advisory Board, Reimbursement of travel costs. Takeda: Reimbursement of travel costs. Novartis: Advisory Board, Reimbursement of travel costs. MedConcept: Honorarium (oral presentation), Reimbursement of travel costs. Beiersdorf: Honorarium (oral presentation), Reimbursement of travel costs. L'Oreal: Honorarium (oral presentation), Reimbursement of travel costs. Merck Sero: Advisory Board, Reimbursement of travel costs. C. Höller: Speaker for Amgen, BMS, MSD, Novartis, Roche; Advisor for Amgen, BMS, Incyte, MSD, Novartis, Pierre Fabre, Roche. Ö. Türeci: Co-founder of Ganymed Pharmaceuticals AG. Member of Scientific Advisory Board of BioNTech AG. J. Utikal: Member of advisory boards and on speakers’ bureaus: Amgen, BMS, GSK, MSD, Novartis, Roche. C. Huber: Co-founder, shareholder, advisor und deputy chairman supervisory board BioNTech. C. Loquai: Advisory board: Roche, Novartis, Pierre Fabre, MSD, BMS, Leo, Amgen, Biontech; Speekers fee: Roche, Novartis, Pierre Fabre, MSD, BMS, Amgen; Travel Reimbursement: Roche, Novartis, MSD, BMS, Amgen. All other authors have declared no conflicts of interest.
Deciphering the intra-tumoural T cell receptor repertoire in patients with NSCLC within the lung TRACERx study
- Kroopa Joshi
- Kroopa Joshi
- James L. Reading
- Mazlina Ismail
- Theres Oakes
- Rachel Rosenthal
- Imran Uddin
- Mariam Jamal-Hanjani
- Nicholas McGranahan
- Yien Ning Sophia Wong
- Andrew J. Furness
- Assma Ben Aissa
- Mariana Werner Sunderland
- Andrew Georgiou
- Selvaraju Veeriah
- Justyna Czyzewska-Khan
- Teresa Marafioti
- Karl Peggs
- Charles Swanton
- Benjamin M. Chain
- Sergio Quezada
Abstract
Background
Our group has previously demonstrated the importance of the clonality of cancer mutations in predicting overall survival in NSCLC and response to checkpoint blockade. Genomic analysis of the first 100 cases within the lung TRACERx study has shown an increased risk of recurrence or death associated with increased intratumoural heterogeneity. Conceivably, the level of mutational burden and genomic heterogeneity could be reflected in the adaptive anti-tumoural immune response in these patients.
Methods
Here, we report TCR sequencing data from multi-region tumour specimens and normal lung in patients within the lung TRACERx study with either genetically heterogeneous (high ITH) or homogenous (low ITH) NSCLC tumours.
Results
We found that the TCR repertoire in tumour specimens is distinct to that observed in normal lung with the majority of CDR3 sequences found to be unique to either compartment, suggestive of a repertoire of T cells spatially confined to the tumour microenvironment, possibly driven by the presence of tumour antigen. We observed a significantly lower degree of overlap in the TCR repertoire between matched normal tissue and tumour tissue compared to the TCR repertoire across multi-region tumour specimens. TCR repertoire heterogeneity was found to reflect neoantigen heterogeneity; we found a significantly higher degree of TCR repertoire overlap, as assessed by the Jaccard index of the 100 most abundant TCRs, in patients with low ITH tumours as compared to high ITH tumours. Moreover, we observed a correlation between TCR clonality and neoantigen load in patients with low ITH tumours.
Conclusions
Taken together, these findings demonstrate a heterogeneous spatial distribution of tumour infiltrating lymphocytes among patients with NSCLC. Theoretically TCR clones, present across multiple regions of the tumour may expand in response to common neoantigens found in all cancer cells and efforts are currently underway to determine the antigen specificity of such TCRs. The observations described are indicative of a dynamic intra-tumoural T cell response that may be accounted for by differences in the genetic heterogeneity in the mutational and predicted neoantigen burden observed in NSCLC.
Funding
None
Disclosure
K. Peggs, S. Quezada: Founder of Achilles Therapeutics. C. Swanton: Receipt of grants/research supports: Pfizer; Receipt of honoraria or consultation fees: Roche Ventana, Celgene, Pfizer, Novartis; Stock shareholder: Grail, Epic Biosciences, Apogen Biotechnologies, Achilles Therapeutics. All other authors have declared no conflicts of interest.
TGF-β signalling attenuates tumour response to PD-L1 checkpoint blockade by contributing to retention of T cells in the peritumoural stroma
- Sanjeev Mariathasan
- Sanjeev Mariathasan
- Shannon J. Turley
- Dorothee Nickles
- Alessandra Castiglioni
- Kobe Yuen
- Yulei Wang
- Kadel Edward E. III
- Hartmut Koeppen
- Jillian L. Astarita
- Rafael Cubas
- Suchit Jhunjhunwala
- Yagai Yang
- Yasin Şenbabaoğlu
- Michiel Van der Heijden
- Yohann Loriot
- Ira Mellman
- Daniel Chen
- Priti Hegde
- Richard Bourgon
- Thomas Powles