Browsing Over 346 Presentations
87P - Clinical outcomes of metastasic melanoma patients treated with ipilimumab and nivolumab: A single institution experience
- H. Oberoi Oberoi (Barcelona, Spain)
- H. Oberoi Oberoi (Barcelona, Spain)
- C. Vila (Sabadell, Spain)
- A. Rodriguez (Barcelona, Spain)
- D. Pesantez Coronel (Barcelona, Spain)
- F. Aya Moreno (Barcelona, Spain)
- M. Font Puig (Barcelona, Spain)
- A. Arance Fernandez (Barcelona, Spain)
Abstract
Background
Immune checkpoint combination therapy with nivolumab and Ipilimumab for untreated metastatic melanoma has shown higher rates of response rates, progression free survival and overall survival compared to monotherapy (Long et al. ESMO 2019), including patients with brain metàstasis, at a cost of higher toxicity. Several clinical factors had been identified as prognostic of response to immunotherapy, such as LDH, dLNR and toxicity.
Methods
We analysed all patients with melanoma treated with ipilimumab and nivolumab between March 2017 and September 2019 institution. Statistical analysis was preformed with IBM SPSS Statistics 24.0.
Results
42 patients (p) treated with ipilimumab and nivolumab were included. 22 (52.4%) men, 38 (90%) ECOG 0-1 (%). Stages at treatment: IVA (n = 4), IVB (n = 11), IVC (n = 17), IVD (n = 9). 20p (48%) presented a positive BRAF mutation. 10p (24%) had a previous adjuvant treatment. LDH: N (n = 25, 60%), <1.2xULN (n = 7, 16%), >1.2xULN (n = 10, 24%). Cycles completed: 1 (n = 4), 2 (n = 16), 3 (n = 7), 4 (n = 12). Best Overall Response (BOR): Progressive disease (n = 22, 52%), stable disease (n = 4, 10%), partial response (n = 10, 24%), complete response (n = 6, 14%). Immunorelated adverse events (irAEs): Yes (n = 27, 64,3%), no (n = 15, 35,7%). Hepatitis 15, colitis 5, hypophysitis 5, thyroiditis 1, Nephritis 1. Grades: 1 (n = 2), 2 (n = 14), 3 (n = 8), 4 (n = 3), Number of CNS lesions: 1 (n = 0), 2 (n = 2), 3 (n = 0) and >3 (n = 8). 9 patients presented CNS disease, 4 of them had symptoms requiring steroid treatment. OS from the whole population was 34.7 months (m) (22.6-46.8, IC 95%). Independent predictors of OS where ECOG (p = 0.1, IC 95%), no previous treatment (p = 0.07, IC 95%), LDH (p = 0.02, IC 95%), irAES (p = 0.05), No 25.6m (8,9-42,4), Yes 39.1m (26.1-52.2), IC 95%). BRAF status, cycles, number of extracranial lesions, number of intracranial lesions and dNLR were not found to be predictors of OS. A significant association was found between BOR and irAEs (p = 0.009), LDH (p = 0.018), ECOG (p = 0.027).
Conclusion
In our cohort, LDH, ECOG and irAEs and no previous treatment were found predictors of response and overall survival. Our median OS and ORR were slighly slower than reported in trials.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
A.M. Arance Fernandez: Honoraria (self): Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
General discussion / Q&A
126TiP - A phase I study of NBTXR3 activated by radiotherapy for patients with advanced cancers treated with an anti-PD-1 therapy
- C. Shen (Chapel Hill, NC, United States of America)
- C. Shen (Chapel Hill, NC, United States of America)
- K. Jameson (Cambridge, United States of America)
- J. Weiss (Chapel Hill, United States of America)
- T. Hackman (Chapel Hill, United States of America)
- D. Corum (Cambridge, United States of America)
- J. Akulian (Chapel Hill, NC, United States of America)
- R. Dixon (Chapel Hill, NC, United States of America)
- A. Pearson (Chicago, IL, United States of America)
- J. Frakes (Tampa, FL, United States of America)
- P. Said (Paris, France)
- H. Miraoui (Cambridge, United States of America)
- E. Baskin-Bey (Paris, France)
- T. Seiwert (Baltimore, AL, United States of America)
Abstract
Background
The majority of cancer patients are resistant to immune therapy; only around 15% respond to immune checkpoint inhibitors (ICI). Thus, strategies able to increase ICI response are of great interest. Recent work suggests radiotherapy (RT) can act as an immunomodulator to increase the proportion of ICI responders and improve clinical outcomes. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. NBTXR3 is a first-in-class radioenhancer administered by intratumoral injection, designed at the nanoscale to increase RT energy dose deposition within the tumor. The result is increased radiation-dependent tumor cell killing, without increasing radiation exposure of healthy tissues. Preclinical and early clinical data suggest NBTXR3 activated by RT can increase the anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect while also producing a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders.
Trial Design
The NANORAY-1100 study is a multicenter, open-label, phase I study that aims to evaluate the safety and tolerability of R3/RT/PD-1 in three cohorts of participants with either: (1) Locoregional recurrent (LRR) or recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the head and neck (HN) field, (2) Lung metastases originating from any primary cancer eligible for anti-PD-1 therapy, or (3) Liver metastases originating from any primary cancer eligible for anti-PD-1 therapy. Participants will be enrolled such that approximately two-thirds of each cohort will be anti-PD-1 non-responders. NBTXR3 injection volume is based on percentage of gross tumor volume (GTV), as determined per central review. The primary objective is to determine the RP2D of R3/RT/PD-1. The secondary objectives are to evaluate the anti-tumor response (objective response rate; ORR) of R3/RT/PD-1, the safety and feasibility of NBTXR3 injection, and the body kinetic profile of NBTXR3. Exploratory objectives will assess biomarkers of response to R3/RT/PD-1, including PD-L1 status by IHC, as well as mRNA and cytokine immune marker profiling.
Clinical trial identification
NCT03589339.
Legal entity responsible for the study
Nanobiotix, SA.
Funding
Nanobiotix, SA.
Disclosure
C. Shen: Honoraria (self): Nanobiotix. K. Jameson: Full / Part-time employment: Nanobiotix. J. Weiss: Honoraria (self): Nanobiotix. T. Hackman: Honoraria (self): Nanobiotix. D. Corum: Full / Part-time employment: Nanobiotix. J.A. Akulian: Honoraria (self): Nanobiotix. R. Dixon: Honoraria (self): Nanobiotix. A. Pearson: Honoraria (self): Nanobiotix. J. Frakes: Honoraria (self): Nanobiotix. P. Said: Full / Part-time employment: Nanobiotix. H. Miraoui: Full / Part-time employment: Nanobiotix. E. Baskin-Bey: Full / Part-time employment: Nanobiotix. T. Seiwert: Honoraria (self): Nanobiotix.
Combining PARP inhibition and immunotherapy in ovarian cancer
- P. Konstantinopoulos (Boston, United States of America)
- P. Konstantinopoulos (Boston, United States of America)
161P - Regulatory interacting network between the immunomodulatory non-coding RNAs: miR-17-5p, MALAT1 and H19 lncRNAs in modulating the tumour microenvironment in TNBC
- R. Soliman (Cairo, Egypt)
- R. Soliman (Cairo, Egypt)
- R. Youness (Cairo, Egypt)
- M. El-Shazly (Cairo, Egypt)
- H. Handoussa (Cairo, Egypt)
- M. Gad (Cairo, Egypt)
Abstract
Background
Triple-negative breast cancer (TNBC) patients are the least fortunate in terms of diagnosis, prognosis and treatment compared to other BC subtypes. Chemotherapy remains the standard treatment, with remarkable rate of resistance. Immunotherapy, on the other hand has shown promising approaches for this aggressive BC subtype. A critical determinant of the success of the immunotherapeutic approaches introduced recently in the clinics is the tumour microenvironment (TME). Our research group has recently highlighted the potential role of IL-10 in shaping the TME of TNBC patients. In this study, we focus on the main pro-inflammatory cytokine, tumour necrosis factor-α (TNF-α), in modulating TME in TNBC cells. In a more translational approach, ncRNAs have been casted as vital regulators of the immune system. A new frontier in the ncRNA world is the cross talk between miRNAs and lncRNAs. In this study, we aimed to investigate the role of microRNA-17-5p and its cross-talk with the oncogenic long non-coding RNAs: MALAT1 and H19 in regulating TNF-α in the TME of TNBC.
Methods
Forty BC patients were recruited. In-silico analysis was performed. MDA-MB-231 cells were cultured and transfected with miR-17-5p oligonucleotides, MALAT1 and H19 siRNAs. Total RNA was extracted and quantified by qRT-PCR. Cellular viability, Colony forming ability and cellular migration were measured using MTT, colony forming assay and scratch assay respectively.
Results
miR-17-5p was down-regulated while MALAT1, H19 and TNF-α were markedly upregulated in TNBC patients. In-silico analysis showed that miR-17-5p binds to MALAT1, H19 and TNF-α. Ectopic expression of miR-17-5p resulted in a significant reduction in H19, MALAT1 and TNF-α. Reciprocally, knocking down of MALAT1 or H19 resulted in a marked induction in miR-17-5p levels. However, MALAT1 and H19 siRNAs decreased TNF-α levels. Functionally, miR-17-5p resulted in a marked reduction in cellular viability, colony forming ability and cellular migration of TNBC cells.
Conclusion
miR-17-5p/MALAT-1/H19/TNF-α represents an immunomodulatory loop that diverts the host immunity in favour of anti-tumour response.
Legal entity responsible for the study
German University in Cairo.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Combining antiangiogenic and immune checkpoint blockade
- J. Bedke (Tübingen, Germany)
- J. Bedke (Tübingen, Germany)
LBA5 - KRAS mutational status and efficacy in KEYNOTE-189: pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC
- D. Rodriguez-Abreu (Gran Canaria, Spain)
- S. Gadgeel (Ann Arbor, United States of America)
- D. Rodriguez-Abreu (Gran Canaria, Spain)
- E. Felip (Barcelona, Spain)
- E. Esteban (Oviedo, Spain)
- G. Speranza (Greenfield Park, QC, Canada)
- M. Reck (Grosshansdorf, Germany)
- R. Hui (Westmead, NSW, Australia)
- M. Boyer (Camperdown, ACT, Australia)
- E. Garon (Santa Monica, CA, United States of America)
- H. Horinouchi (Chuo-ku, Japan)
- R. Cristescu (Kenilworth, United States of America)
- D. Aurora-Garg (Kenilworth, New Jersey, United States of America)
- J. Lunceford (Kenilworth, NJ, United States of America)
- J. Kobie (Kenilworth, United States of America)
- M. Ayers (West Point, United States of America)
- B. Piperdi (Whitehouse Station, United States of America)
- M. Pietanza (Whitehouse Station, NJ, United States of America)
- M. Garassino (Milan, Italy)
Abstract
Background
KRAS mutations are observed in ~25% of lung adenocarcinomas, with some studies suggesting it is a prognostic factor in NSCLC. We assessed the prevalence of KRAS mutations and their association with efficacy in an exploratory analysis of the KEYNOTE-189 study of pembrolizumab plus pemetrexed and platinum chemotherapy vs placebo plus chemotherapy as first-line therapy for metastatic nonsquamous NSCLC (NCT02578680).
Methods
Whole-exome sequencing (WES) was used to assess KRAS status and tumor mutational burden (TMB) in participants (pts) who had available tumor and matched-normal tissue. Descriptive analyses of the association of KRAS and KRAS G12C status with efficacy were included as part of this exploratory analysis, as was correlation between KRAS mutational status and shifts in TMB and PD-L1 expression distributions.
Results
289 (47%) of 616 pts had evaluable WES data from both tumor and normal DNA. 89 (31%) of 289 pts had KRAS mutation, including 37 (13%) G12C carriers. Pts with vs without KRAS mutations tended to have higher PD-L1 TPS (median [IQR] 30% [1-71] vs 5% [0-60]) and higher TMB (median [IQR] 204 [137-276] vs 141 [85-252] mut/exome). Outcomes of pembrolizumab plus chemotherapy and of placebo plus chemotherapy in pts with and without KRAS mutation and in KRAS G12C carriers are summarized in the Table. 95% CIs were wide given the modest frequency of KRAS mutation, particularly KRAS G12C, and the 2:1 randomization that resulted in small populations for placebo plus chemotherapy.
Conclusion
Based on this descriptive exploratory analysis, pembrolizumab plus pemetrexed and a platinum should be a standard first-line treatment for pts with metastatic nonsquamous NSCLC regardless of KRAS mutation status.
| With Any KRAS Mutation | With KRAS G12C Mutation | Without Any KRAS Mutation | ||||
| Pembro + Chemo (N = 59) | Placebo + Chemo (N = 30) | Pembro + Chemo (N = 26) | Placebo + Chemo (N = 11) | Pembro + Chemo (N = 145) | Placebo + Chemo (N = 55) | |
| ORR, % (95% CI) | 40.7 (28.1-54.3) | 26.7 (12.3-45.9) | 50.0 (29.9-70.1) | 18.2 (2.3-51.8) | 47.6 (39.2-56.0) | 10.9 (4.1-22.3) |
| PFS, median, mo (95% CI) | 9 (7-14) | 5 (5-9) | 11 (6-18) | 5 (5-NR) | 9 (7-14) | 5 (4-5) |
| PFS, HR (95% CI) | 0.47 (0.29-0.77) | 0.48 (0.22-1.06) | 0.40 (0.29-0.57) | |||
| OS, median, mo (95% CI) | 21 (16-NR) | 14 (8-NR) | 18 (11-NR) | 25 (8-NR) | 23 (19-NR) | 9 (7-17) |
| OS, HR (95% CI) | 0.79 (0.45-1.38) | 1.14 (0.45-2.92) | 0.55 (0.37-0.81) | |||
Clinical trial identification
KEYNOTE-189, NCT02578680
Editorial acknowledgement
Joanne Tomassini and Melanie Leiby, both of Merck & Co., Inc., Kenilworth, NJ, USA, for writing support.
Status of CAR T-cells for cancer
- C. June (Philadelphia, PA, United States of America)
- C. June (Philadelphia, PA, United States of America)
DOI session
8P - The prognostic value of tumour-infiltrating lymphocytes (TILs) in pancreatic cancer: A systematic review and meta-analysis
- A. Orhan (Copenhagen, Denmark)
- A. Orhan (Copenhagen, Denmark)
- R. Vogelsang (Koege, Denmark)
- M. Andersen (Koege, Denmark)
- M. Madsen (Koege, Denmark)
- E. Hölmich (Koege, Denmark)
- H. Raskov (Koege, Denmark)
- I. Gögenur (Koege, Denmark)
Abstract
Background
Pancreatic cancer (PC) contributes to over 7 % of all cancer related deaths worldwide with a relative 5-year survival of less than 8 %. High levels of tumor-infiltrating lymphocytes (TILs) are associated with improved survival in many cancer types. Examining the impact of TILs on survival in PC could provide better prognostication and help clinicians tailor therapy for patients.
Methods
A systematic search based on the PICO-process was conducted on PubMed, Embase, The Cochrane Library and Web of Science. Outcome of interest was overall survival (OS). Studies examining high vs. low levels of TILs in pancreatic tumor tissue and its impact on OS was included. Following data extraction a random-effects model meta-analysis was conducted on the reported outcome with corresponding lymphocyte subset. The Newcastle-Ottowa Scale was used for study quality assessment.
Results
In total, 43 studies were included in the systematic review and 40 were eligible for meta-analysis. A time-to-event meta-analysis on the different lymphocyte subtypes revealed, that high vs. low infiltration of CD3+ T and CD8+ T cells was significantly associated with improved OS (HR = 0.59, 95 % CI: 0.51 - 0.68, I2: 0 % and HR = 0.61, 95 % CI: 0.57 – 0.67, I2: 0 %, respectively). High infiltration of FoxP3+ T cells was associated with decreased OS (HR = 1.41, 95 % CI: 1.15 – 1.73, I2: 85 %). The prevalence of CD4+ and CD20+ lymphocytes in pancreatic tumor tissue was not significantly associated with increased OS (HR = 0.87, 95 % CI: 0.65 - 1.17, I2: 80 % and HR = 0.86, 95 % CI: 0.54 – 1.35, I2: 66 %, correspondingly).
Conclusion
High infiltration of CD3+ and CD8+ lymphocytes is associated with improved OS among patients with resected PC, whereas high infiltration of FoxP3+ T cells is associated with decreased OS. CD4+ and CD20+ lymphocytes did not have a significant impact on OS. Based on these findings, staining for TILs, especially CD3+, CD8+ and FoxP3+ T cells, might be an important tool for future assessment of patient survival and prognosis, as well as for tailored oncological therapy.
Clinical trial identification
CRD42019134744.
Legal entity responsible for the study
The authors.
Funding
Center for Surgical Science.
Disclosure
All authors have declared no conflicts of interest.
42P - GMP-compliant human monocyte-derived dendritic cells for cancer vaccination generated by using the Quantum® hollow fiber bioreactor system
- U. Uslu (Erlangen, Germany)
- U. Uslu (Erlangen, Germany)
- M. Erdmann (Erlangen, Germany)
- M. Wiesinger (Erlangen, Germany)
- G. Schuler (Erlangen, Germany)
- B. Schuler-Thurner (Erlangen, Germany)
Abstract
Background
The Quantum® hollow fiber bioreactor system represents a platform integrating GMP-compliant manufacturing steps in a closed system for automated cultivation of cellular products. A previous report to generate monocyte-derived DCs (Mo-DCs) for cancer immunotherapy involved fibronectin-coating of the hollow-fibers and trypsin digestion to harvest cells and proved unsatisfactory as only one tenth of an apheresis product could be processed. Thus, optimization of this approach is needed.
Methods
Monocytes were enriched by using the Elutra® cell separation system and were differentiated over 6 days into immature DC in the presence of GM-CSF + IL-4, and then exposed to a maturation cocktail to generate mature Mo-DCs. This was performed in parallel either by using the Quantum® or by our in-house established standard protocol in cell culture bags. Phenotype, antigen presentation, and functionality of these Mo-DCs were then analyzed and compared.
Results
Intitial tests with the Quantum® were performed to avoid the initial fribronectin coating and trypsin digestion for harvesting of cells, which required optimization of media exchange rate, cytokine concentration and cytokine addition. Under optimized conditions, cells cultured in the Quantum® resulted in a yield of 27.8% mature DCs (related to input monocytes) with CD83 expression in 92.0% of these cells. Total yield of mature Mo-DCs was slightly higher when the in-house established standard protocol was used. Survival of Mo-DCs analyzed in the washout test (24 hour culture in medium without cytokines) was comparable with both methods. Cell surface CD80, CD83, CD86, and HLA-DR expression was in general higher in DCs generated by our standard protocol. GFP-electroporated Mo-DCs generated by Quantum®, however, showed a trend towards higher GFP- expression as well as towards higher T-cell stimulation and proliferation in the primary allogeneic MLR-assay.
Conclusion
We have adapted the Quantum® system to process one complete apheresis product to yield a large number of mature and functional GMP-compliant monocyte-derived DCs for the use in cancer immunotherapy without any need for fibronectin coating or trypsin digestions.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
78P - A systematic review and meta-analysis of trials assessing activity of PD-1/PD-L1 immune checkpoint inhibitors (ICIs) for pre-treated advanced malignant mesothelioma (aMM)
- M. Tagliamento (Orbassano, Italy)
- M. Tagliamento (Orbassano, Italy)
- P. Bironzo (Orbassano, Italy)
- E. De Luca (Turin, Italy)
- D. Pignataro (Orbassano, Italy)
- S. Rapetti (Orbassano, Italy)
- M. Audisio (Turin, Italy)
- V. Bertaglia (Orbassano, Italy)
- C. Paratore (Orbassano, Italy)
- M. Bungaro (Orbassano, Italy)
- E. Olmetto (Orbassano, Italy)
- E. Artusio (Orbassano, Italy)
- M. Reale (Orbassano, Italy)
- C. Zichi (Turin, Italy)
- E. Capelletto (Orbassano, Italy)
- S. Carnio (Orbassano, Italy)
- L. Buffoni (Orbassano, Italy)
- F. Passiglia (Orbassano, Italy)
- S. Novello (Orbassano, Italy)
- M. Di Maio (Turin, Italy)
Abstract
Background
aMM still represents a hard-to treat disease, due to its rarity and to the modest activity of standard chemotherapy. Recently, ICIs directed against PD-1/PD-L1 have been tested in clinical trials in chemotherapy pre-treated aMM patients, but their efficacy is still debatable.
Methods
We searched PubMed and proceedings of major meetings, to perform a systematic review and meta-analysis (updated at September 30th 2019) of clinical trials testing ICIs in this setting, describing activity in terms of Objective Response Rate (ORR) and Disease Control Rate (DCR). To explore the potential predictive role of PD-L1 expression, we also collected the ORR in subgroups of patients selected for PD-L1 expression (based on the highest cut-off used in each study).
Results
8 studies were selected (1 phase III, 4 phase II, 2 phase IB, 1 real-world EAP data study), including 405 patients, most with pleural MM; 1 registry study was excluded due to inclusion of treatment-naive patients, 1 due to unclear inclusion criteria. 352 patients (87%) were treated with anti-PD-1 (nivolumab [N] or pembrolizumab [P]), 53 (13%) with anti-PD-L1 (avelumab [A]). Overall, ORR was 19.6% (95% CI, 16.0-23.8%) with no significant difference among drugs (N 20.0%, P 22.6%, A 9.4%; p = 0.11); DCR was 56.5% (95% CI, 51.6-61.3%) with no significant difference among drugs (N 54.0%, P 58.7%, A 58.5%; p = 0.66). When restricting the analysis to patients selected for PD-L1 expression (n evaluable=91, based on cut-offs ranging from 1% to 50% in different trials), ORR was 34.1% (95% CI, 25.2-44.3%), ranging from 18.8% to 71.4% in different trials. In unselected patients, median progression-free survival ranged from 2.5 to 6.1 months, and median overall survival ranged from 6.36 to 17.3 months.
Conclusion
To our knowledge, this is the first meta-analysis synthesizing the evidences of activity of PD-1/PD-L1 ICIs in pre-treated aMM. ORR and DCR in unselected patients are encouraging compared to historical results with second-line chemotherapy. Selection based on PD-L1 expression could increase the activity of immunotherapy, but trials were heterogeneous for test and cut-off.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
M. Tagliamento: Travel / Accommodation / Expenses: Takeda, Bristol-Myers Squibb, Roche. P. Bironzo: Honoraria (self): Bristol-Myers Squibb, BI, AstraZeneca. E. Capelletto: Advisory / Consultancy: BI, AstraZeneca. S. Novello: Speaker Bureau / Expert testimony: AstraZeneca, Abbvie, Celgene, BI, Bristol-Myers Squibb, MSD, Eli Lilly, Pfizer, Roche. M. Di Maio: Honoraria (self): Bristol Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, Janssen, Takeda, Pfizer; Honoraria (institution): Tesaro. All other authors have declared no conflicts of interest.