PD1 inhibitors as well as PD1/CTLA4 combinations have shown remarkable efficacy in the first-line treatment of metastatic melanoma. The impact of many concomitant medications on the clinical outcomes from PD1 based therapies remains elusive.
We retrospectively analyzed 140 patients included in the Checkmate 069 phase II clinical trial as a discovery cohort, comparing ipilimumab monotherapy with ipilimumab combined with nivolumab. We compared response rates, progression-free survival and overall survival of patients treated or not with 11 different classes of co-medications at immune therapy initiation. Disease stage, LDH levels, BRAF status, sex, age, and body mass index were also compared. Furthermore, a protein array was performed for 440 analytes in a subset of 135 patients for whom pretreatment serum was available. We validated the impact of proton pump inhibitors in an independent cohort of 68 PD1 monotherapy (pembrolizumab or nivolumab) treated patients.
In univariate analysis, baseline proton pump inhibitor treatment almost halved the objective response rates, reduced progression-free and overall survival of patients treated with ipilimumab and nivolumab but not with ipilimumab alone. This effect was maintained when accounted for multiple comparisons and in a multivariate analysis. Pretreatment serum protein analysis showed increased NCAM1 and CSF3R levels in PPI users. We found increased baseline blood leukocyte and neutrophil levels in correlation with PPI use. The results were confirmed in an independent cohort of 68, first-line melanoma patients.
Our analysis shows that proton pump inhibitors could negatively impact on the benefit from PD1 based therapies both for monotherapy and also for ipilimumab and nivolumab combination therapy. PPIs might establish a unique inflammatory immune status, prior to immune therapy initiation that interferes with treatment efficacy. These results suggest that if possible PPIs should be avoided in patients who are destined for PD1-based immunetherapies. Also, the results will have important implication for design of future clinical trials.
Department of Oncology, CHUV, Lausanne, Switzerland.
Has not received any funding.
M. Wind-Rotolo: Employee of BMS. All other authors have declared no conflicts of interest.
Outcome of high-risk stage III melanoma patients (pts) has been poor, with a 5-year overall survival (OS) rate of < 50%. Adjuvant IPI improved 5-year relapse-free survival (RFS) and OS and adjuvant (adj) anti-PD1 improved RFS further. Neoadjuvant (neoadj) IPI + NIVO has been shown in 3 investigator-initiated trials to induce high pathologic response rates. While standard dosing regimen of IPI 3mg/kg + NIVO 1mg/kg has been too toxic for broader application, OpACIN-neo identified 2 courses IPI 1mg/kg + NIVO 3mg/kg as well tolerated and effective scheme to proceed to phase 3. Pathologic response was a good predictor for early outcome (none of the pts relapsed), but longer follow-up (FU) data are missing so far.
Between August 2015 and October 2016, 20 high risk, stage IIIB/IIIC melanoma pts with palpable nodal disease were included in the phase 1b feasibility OpACIN trial. Pts were randomized to receive IPI 3mg/kg plus NIVO 1mg/kg, either adj 4 courses, or split 2 courses neoadj and 2 adj. Pathological response was reviewed by a blinded pathologist, response was defined as < 50% viable tumor cells. The study was not powered to compare both arms, all efficacy endpoints are descriptive.
After a median FU of 31.6 months (minimum 23.5 months FU of pts alive) none of the 7 pts that achieved a pathologic response in the neoadj arm have relapsed. Two non-responding pts in the neoadj arm have relapsed, and 4 pts in the adj arm. 1 pt died in the neoadj arm and 3 in the adj arm. Estimated 30 months RFS rates were 80% for the neoadj arm and 60% for the adj arm and 30 months OS rates were 90% and 67%, respectively. Of the 18 (90%) pts that had developed one or more grade 3-4 adverse events, all recovered to ≤ grade 1, except for grade 2 endocrine toxicities needing hormonal suppletion therapy that are ongoing in 8 (50%) of 16 pts alive.
OpACIN was the first trial investigating neoadj IPI + NIVO in pts with macroscopic stage III melanoma, thus having the longest FU. None of the pts with a pathologic response has relapsed, suggesting that this could become a primary read-out for subsequent neoadj immunotherapy trials and a surrogate marker for RFS and OS.
NCT02437279.
Netherlands Cancer Institute.
BMS.
E.A. Rozeman: Travel support: MSD, NanoString. H.V. van Thienen: Travel support: Roche. D. Peeper: Research support: BMS. J.B.A.G. Haanen: Fees to NKI for advisory roles: BMS, MSD, Roche, Neon Therapeutics, Immunocore, Novartis, AstraZeneca/MedImmune, Pfizer, Ipsen; Grants to NKI: BMS, Merck, Novartis, Neon Therapeutics. A.C.J. van Akkooi: Personal fees for advisory role: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer; Grants: Amgen, Novartis, all outside the submitted work. T.N. Schumacher: Consultant: Adaptive Biotechnologies, AIMM Therapeutics, Amgen, Neon Therapeutics, Scenic Biotech; Grant/research support: Merck, BMS, Merck KGaA; Stockholder: AIMM Therapeutics, Neon Therapeutics. C.U. Blank: Personal fees for advisory roles: MSD, BMS, Roche, GSK, Novartis, Pfizer, Lilly; Grants: BMS, Novartis. All other authors have declared no conflicts of interest.
test
EBV+ LMS is a rare cancer that develops in patients with immune deficiency. EBV+ LMS responds poorly to radiation and chemotherapy resulting in limited treatment options and poor outcomes.1 Tabelecleucel is an investigational, off-the-shelf, genetically unmodified, allogeneic T-cell immunotherapy targeting EBV antigens. Here we report the efficacy and safety of tabelecleucel in a subgroup of EBV+ LMS patients from 3 clinical trials.
test
Tabelecleucel was evaluated in 2 single-center, open-label studies (NCT00002663 [Study 1], NCT01498484 [Study 2]) and a multi-center expanded access protocol (NCT02822495 [Study 3]). Tabelecleucel was given at 1.0–2.0 x 106 cells/kg/dose on days 1, 8, and 15 of every 4-6-week cycle, and imaging was performed before the 1st dose of each cycle.
A total of 12 patients with EBV+ LMS received ≥ 1 dose of tabelecleucel, 10 of whom were assessed for responses (1 patient was not evaluable and 1 patient was too early to assess). Using CT-based RECIST 1.1 criteria, 2 patients achieved a partial response (objective response rate = 17%) and 8 patients achieved stable disease. In studies 1 and 2 where longer follow-up is available, 6 of 8 patients survived ≥ 27 months. The median survival (95% CI) is 77.4 (18, NE) months. At the time of this analysis, metabolic responses were available in study 3: 3 of the 4 patients (75%) achieved a metabolic response. The safety profile is consistent with previously reported data;2 no new safety signals have been identified.
This analysis represents one of the larger prospective studies of patients with EBV+ LMS. The combination of CT-based and metabolic responses to tabelecleucel, in the context of prolonged survival, demonstrate that tabelecleucel (also known as tab-cel™) may provide clinical benefit in this typically radiation- and chemotherapy-resistant disease. Tabelecleucel is well tolerated in this population of patients. References: 1. Wang Z et al. Cancer Med. 2016;5(12):3437-3444. 2. Prockop SE et al. Blood. 2017;130:4520.
Editorial assistance in the writing of this abstract was provided by Kathryn Boorer, PhD of KB Scientific Communications, LLC.
NCT00002663, NCT01498484, NCT02822495.
Atara Biotherapeutics and Memorial Sloan Kettering Cancer Center.
Atara Biotherapeutics and Memorial Sloan Kettering Cancer Center.
S. Suser: Research funding: Atara Biotherapeutics. E. Doubrovina: Royalties following licensure of the EBV-specific T-cell bank: Atara Biotherapeutics; Research support and consultant fees: Atara Biotherapeutics. A. Sudhindra, Y. Wei, M. Hiremath, W. Navarro: Employee and stock holder: Atara Biotherapeutics. R. O\'Reilly: Royalties following licensure of the EBV-specific T-cell bank: Atara Biotherapeutics; Research support and consultant fees: Atara Biotherapeutics. S. Prockop: Research funding: Atara Biotherapeutics. All other authors have declared no conflicts of interest.
Intersecting genetic, biologic and clinico-pathological features with high-throughput imaging may pave the way to precision oncology. We advanced the hypothesis that the tumor immune microenvironment (TIME) may imprint on CT scan parameters in a qualitative and quantitative (radiomics) fashion, providing a non-invasive approach to identify new prognostic factors in NSCLC patients.
In this study, we enrolled sixty (31 Adenocarcinoma, 29 Squamous Cell Carcinoma) surgically resected patients. We defined TIME by the quantitative assessment of PD-L1 expression and a detailed morphometric evaluation of Tumor Infiltrating Lymphocytes (TILs). Next, from each tumor associated images we extrapolated 841 CT radiomic features through an open-source (3d Slicer) software.
We observed high levels of tissue PD-L1 in radiologic lesions displaying a solid texture and any effect on the surrounding parenchyma (p < 0.05), while well defined CT margins were seen in TILs-rich cases (p < 0.05). The combined analysis of predetermined risk factors from TIME and CT texture had a striking impact on clinical outcome. Patients with low PD-1 expression on CD8+ TILs and CT evidence of tumor effect on parenchyma had significantly increased (p < 0.001) OS with respect to their counterpart (median 50 vs 30 months, HR = 16.82). We also documented prolonged survival (p < 0.05) in cases with well defined CT margins and high CD8-to-CD3 TILs (46 vs 35 months, HR = 2.66). Intriguingly, when an unsupervised hierarchical clustering model was applied to radiomics data, we identified two clusters (A and B) with oppositely regulated features: the first of 57 cases (A), further branching into two continuous different clusters, the second (B) comprised only three patients sharing a mutual genetic (EGFR and KRAS mutations), immunologic (PD-L1, CD3+ and CD8+ TILs, PD-1/CD8 ratio), radiologic (shape, effect, texture and structure) and clinical (relapse and death) profile.
A highly significant prognostic score can be obtained in NSCLC by integrating TIME with CT features. Distinct tissue immune backgrounds may entail imaging textures potentially able to portray a radiologic signature of lung cancer.
University of Parma.
Has not received any funding.
All authors have declared no conflicts of interest.
Despite CAR-T cell therapy achieving remarkable results in the treatment of lymphoma, treatment of solid tumor using CAR-T remains an enormous challenge. It has been proposed that combinational immune-therapy may be a more efficacious approach to solid tumors. In this study, we combined anti-MUC1 CAR-T cell with PD-1 knockout (KO) T cells to treat advanced NSCLC. This represents the first attempt in the treatment of human solid cancer using PD-1 (KO) technology.
Patients were recruited according to the criteria in NCT03525782. MUC1-specific CARs were constructed using the SM3 scFv. Following lenti-MUC1 CAR retroviral transduction, efficiency of transgenic expression was assessed by flow cytometry. PD-1 gene KO in the CAR positive T cells was achieved using the CRISPR-Cas9 system and validated by sequencing. MUC1-CAR+/PD-1- KO engineered T cells at a dose of 2.5x106/KG were infused over 60 mins. Following treatment, patients’ general condition, levels of lymphocytes, IL-6, hs-CRP, PCT, CYFRA21, NSE(E), and SCC were monitored at regular intervals. Changes in tumor size were examined by MRI scans.
8 patients (aged 36 to 84) diagnosed with NSCLC (IIIb to IV), were recruited for this study. Data from 6 patients are included in this report. All patients had significant symptom improvements in the first 2 weeks after infusion. Serum CYFRA 21 declined following infusion and subsequently increased 4 weeks after treatment. Changes in tumor size varied between patients. In 2/6 patients, lung tumor size shrunk significantly within 4 weeks after treatment (one reduced from 25x19x22mm to 14x10x26mm). The effect on metastasis was limited. No CRS was observed although cytokine levels increased in 3/6 patients. No other adverse effects were recorded in all patients.
Our data suggests that combined MUC1-CAR+/PD-1-KO therapy is safe and well tolerated by all patients and importantly no CRS was indicated in all cases. The efficacy of the combined therapy was case specific: some NSCLC patients responded well, while no noticeable response observed in others. This marked individual patient response to treatment indicates that other unknown factors, confer more sensitivity in a sub-set of patients.
No
NCT03525782.
Guangzhou Anjie Biomedical Technology Co. Ltd.
Has not received any funding.
All authors have declared no conflicts of interest.
Pembrolizumab monotherapy was approved for first-line (1L) treatment of metastatic non-small cell lung cancer (NSCLC) with PD-L1 tumor proportion score (TPS) ≥50% in October 2016 in the US, based on the findings from KEYNOTE-024 trial. A recent update of the trial with 25.2 months median follow-up demonstrated median pembrolizumab treatment duration of 7.9 months. The objective of our study is to estimate real-world time on treatment (rwToT) for 1L pembrolizumab monotherapy in a clinically matched real-world NSCLC database.
This retrospective study utilized the Flatiron Health EHR-derived advanced NSCLC database from which patients with stage IV diagnosis, TPS ≥50%, at least one dose of 1L pembrolizumab monotherapy, and ECOG performance status (PS) 0-2 were included. Patients with missing or ECOG PS > 2 were excluded. rwToT was defined as the length of time between first and last administration date of pembrolizumab. Patients with a record of next line of therapy, or death, or whose last activity date was ≥120 days from the last administration date were considered discontinued; others were censored. The Kaplan-Meier (KM) estimates were generated for median rwToT, restricted mean (rMean) rwToT at maximum time point where at least 10% of patients have not discontinued, and landmark on-treatment rates. rMean rwToT at 24 months was also computed using the parametric function that provided best fit based on statistical testing and visual inspection criterion. All results were stratified into ECOG PS 0-1 (similar to KEYNOTE-024) and ECOG PS 2. Flatiron dataset from 31-Jul-2018 with median follow-up of 10.8 months was utilized.
Real-World Time on Treatment and On-Treatment Rate for First-Line Use of Pembrolizumab Monotherapy in Stage IV NSCLC, TPS ≥50%ECOG 0-1 ECOG 2 N 454 172 Mean age, years 70.7 72.7 N discontinued pembrolizumab (%) 220 (48.5) 114 (66.3) Median rwToT in months (95% CI) 6.9 (5.7, 8.5) 2.3 (1.4, 3.1) rMean rwToT in months (95% CI) 6.9 (6.4, 7.4) [@12 months] 3.7 (3.2, 4.3) [@9 months] Extrapolated rMean rwToT @ 24 months (95% CI) 10.4 (9.3, 11.8) [Weibull] 6.6 (4.8, 8.4) [Log Normal] 6 months On-treatment rate in % (95% CI) 54.1 (48.8, 59.1) 32.0 (24.3, 39.9) 12 months On-treatment rate in % (95% CI) 36.8 (31.0, 42.6) -/- 18 months On-treatment rate in % (95% CI) 31.7 (25.2, 38.4) -/-
In the real-world, duration of pembrolizumab use for 1L metastatic NSCLC is similar to KEYNOTE-024 when restricted to a trial-matched population of ECOG 0-1 patients. Duration of use tended to be however shorter in a real-world population of ECOG 2 patients who are commonly excluded from clinical trials.
Funding and support for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
V. Velcheti: Advisory/consultant role: Merck, Bristol-Myers Squibb, AstraZeneca, Genentech, Celgene, Takeda, Foundation Medicine, Nektar Therapeutics. S. Chandwani, X. Chen, M.C. Pietanza, T. Burke: Employee and shareholder: Merck & Co., Inc., Kenilworth, NJ, USA.
Tislelizumab, a humanized IgG4 monoclonal Ab with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages, thus abrogating antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports from this first-in-human study (NCT02407990), and other early phase studies, suggested tislelizumab was generally well tolerated and had antitumor activity in pts with advanced solid tumors. Here we report the effects of tislelizumab in a subset of pts enrolled in phase 1A/1B.
Eligible patients with advanced esophageal [EC], gastric [GC], hepatocellular [HCC], and non-small cell lung [NSCLC] cancers were treated with tislelizumab 2 or 5 mg/kg every 2 wks or 3 wks (Q3W); 97% received 5mg/kg Q3W. Adverse events (AEs) were assessed per NCI-CTCAE 4.03 criteria and tumor assessments performed every 9 wks using RECIST v1.1.
Of the 207 pts (EC = 54; GC = 54; HCC = 50; NSCLC = 49), 114 were male, 111 were Asian, 78 were Caucasian and all but one received ≥1 prior anticancer therapy. Treatment-related AEs (TRAEs) occurring in ≥5% of pts were fatigue (8.7%), decreased appetite (6.8%), rash (6.8%), hypothyroidism (6.3%), and nausea (6.3%). Grade ≥3 TRAEs occurring in ≥2 pts were pneumonitis (n = 3), elevated AST (n = 3), and elevated ALT (n = 2). Grade 5 TRAEs occurred in two pts: pneumonitis in a pt with NSCLC with compromised pulmonary function and acute hepatitis in a pt with HCC with rapidly progressing disease. As of 27 Apr 2018, a total of 23 pts remained on study treatment; median duration of study follow-up ranged from 4.9–9.9 mo. Responses in each tumor type are presented in the table.
Tislelizumab was generally well tolerated and antitumor activity was observed in each tumor type. Tislelizumab, as monotherapy and in combination, is being evaluated in multiple phase 2 and phase 3 studies.
Medical writing and editorial assistance was provided by Regina Switzer, PhD (SuccinctChoice Medical Communications, Chicago, IL).
NCT02407990.
BeiGene, Ltd.
Beigene, Ltd.
S. Deva: Travel, accomodations, expenses: Roche. M. Millward: Research funding to institution: Beigene; Consulting or advisory role: AstraZeneca, Roche, BMS, MSD; Travel, accomodations, expenses: Roche, BMS, MSD. M. Jameson: Research funding: Beigene, Merck, Dynavaz, Pfizer to institution; Travel, accomodations, expenses: Merck. Y. Kang: Research funding: Roche; Consulting or advisory roles: Novartis, Roche, BMS, Ono, Blueprint, Daehwa. B. Markman: Consulting or advisory role: Novartis. L. Horvath: Speakers bureau: Janssen-Cilag; Research funding: Astellas. M. Friedlander: Honoraria: AstraZeneca, MSD; Consulting or advisory role: AstraZeneca, MSD; Research funding: BeiGene (Inst). A. Hill: Employment, stock, other ownership interests, research funding: Tasman Oncology; Travel, accommodations, expenses: Bristol-Myers Squibb. J. Wu, J. Hou: Employee of BeiGene. J. Desai: Consulting or advisory role: Amgen, Beigene, Bionomics, Eisai, Lilly, Novartis; Research funding: Bionomics (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Roche (Inst). All other authors have declared no conflicts of interest. ORR = CR + PR; DCR = CR + PR + SD. Abbreviations: CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.Best Overall Response, Confirmed EC N = 53 GC N = 52 HCC N = 49 NSCLC N = 44 CR, n 1 0 0 0 PR, n 5 7 6 6 SD, n 14 9 19 23 PD, n 25 31 23 12 Not evaluable/missing, n 8 5 1 3 ORR, % (95% CI) 11.3 (4.3, 23.0) 13.5 (5.6, 25.8) 12.2 (4.6, 24.8) 13.6 (5.2, 27.4) DCR, % (95% CI) 37.7 (24.8, 52.1) 30.8 (18.7, 45.1) 51.0 (36.3, 65.6) 65.9 (50.1, 79.5)
Tumor mutation burden (TMB) has emerged as a promising predictive biomarker for anti-PD1/L1; however, whether somatic mutations in specific genes can sensitize to immunotherapy is poorly understood. We explored association between mutations detectable in circulating tumor DNA (ctDNA) and outcomes on anti-PDL1 (D; durvalumab) therapy.
NCT01693562, NCT02087423, and NCT02207530 were nonrandomized phase 2 trials evaluating D (10 mpk Q2W) in pts with advanced solid tumors, NSCLC, or PDL1+ HNSCC, respectively. Using a next-generation sequencing panel comprised of 73 genes, we examined ctDNA mutations in a discovery set of 116 NSCLC and 33 urothelial carcinoma (UC) pre-treatment. Seven genes were identified harboring muts that enriched for response (RECIST v1.1). These genes were tested in a validation cohort of 217 NSCLC, 130 UC, 48 gastroesophageal, 36 HCC, 52 MSI+, 40 ovarian, 32 pancreatic, 50 HNSCC, 34 TNBC, 16 SCLC, 18 ST sarcoma, 21 HPV cancers, 22 uveal melanoma, 18 cutaneous melanoma and 6 nasopharyngeal carcinoma.
In the discovery cohort, pts who responded to D had higher prevalence of muts in BRCA2, NFE2L2, NOTCH1, PIK3CA, ARID1A, APC, and BRCA1 compared to non-responders (OR = 1.3-9). Consistent associations with BRCA2, NFE2L2, NOTCH1 and ARID1A muts and response were observed in the validation cohort comprised of multiple tumor types (OR = 1.9-2.3; Table 1). Pts in the validation cohort with BRCA2 muts had longer numerical median DoR of 12.4 compared to wildtype of 8.4 months across all tumors. Muts in NFE2L2 occurred in the Neh2 domain, which binds the negative regulator KEAP1, activating this transcription pathway. Muts in these genes were associated with significantly higher TMB in multiple tumor types in TCGA. Prevalence ranged from 0-26% or 0-20% in TCGA or a ctDNA clinical database, respectively.
Somatic muts in specific genes sensitize to anti-PDL1 treatment in multiple tumor types (Table). Objective response by genes harboring muts in validation cohortGene (mut type) Mutant N, ORR % (95% CI) Wildtype N, ORR % (95% CI) p BRCA2 (inactivate) 70, 26% (16%, 38%) 670, 13% (11%, 16%) 0.006 NFE2L2 (activate) 30, 27% (12%, 46%) 710, 14% (11%, 16%) 0.059 NOTCH1 (both) 39, 23% (11%, 39%) 701, 14% (11%, 16%) 0.10 ARID1A (inactivate) 122, 21% (4%, 48%) 618, 13% (10%, 16%) 0.022
Editorial support was provided by Guardant Health.
NCT01693562/September 26, 2012; NCT02087423/March 14, 2014; NCT02207530/August 4, 2014.
MedImmune.
MedImmune.
M. Kuziora: Employed by MedImmune; Stock: AstraZeneca; Patent B7H1-410-US-PSP pending. B. Higgs: Employed by MedImmune; Stock: AstraZeneca; Intellectual property interests: MedImmune. P. Brohawn, K. Streicher, R. Raja: Employed by MedImmune; Stock: AstraZeneca. M. Jure-Kunkel: Employed by MedImmune; Stock: AstraZeneca; Patents, royalties, or other intellectual property: Bristol-Meyers Squibb. E. Helman: Employed by, stock, intellectual property interests: Guardant Health. A. Franovic: Employed by Guardant Health. Z. Cooper, Y. Shrestha: Employed by MedImmune. Y. Lee: Employed by MedImmune; Stock: AstraZeneca. P. Mukhopadhyay, P.A. Dennis: Employed by, stock: AstraZeneca. G. Melillo: Employed by AstraZeneca. S.E. Abdullah: Employed by, travel, accommodations, or other expenses: MedImmune; Stock: AstraZeneca. K. Ranade: Employed by, intellectual property interests: MedImmune; Stock: AstraZeneca. All other authors have declared no conflicts of interest.