bluuebunny/crossref_metadata_2025 huggingface dataset:
Anakinra (AKR) prophylaxis (ppx) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) receiving orvacabtagene autoleucel (orva-cel).
Authors: Costa Luciano J. , Mailankody Sham , Shaughnessy Paul , Hari Parameswaran , Kaufman Jonathan L. , Larson Sarah Marie , Dingli David , Lee Kelvin , Conte Kristin , DeVries Todd , Piasecki Julia , Li Meng , Dubowy Ronald L. , Htut Myo
Published: June 2021

2537

Background: Orva-cel is a B-cell maturation antigen–targeted chimeric antigen receptor (CAR) T cell therapy being evaluated in the phase 1/2 EVOLVE study (NCT03430011) in pts with RRMM who had at least 3 prior lines of therapy (Tx). We previously reported safety and efficacy in the phase 1 study and established the recommended dose (RD) of orva-cel as 600 × 106 CAR+ T cells (Mailankody et al, ASCO 2020). Cytokine release syndrome (CRS), a dominant toxicity of CAR T cell therapy, is mediated in part by IL-1. We explore the role of ppx with AKR, an IL-1 signaling inhibitor, on reducing the incidence of grade (G) ≥2 CRS after orva-cel treatment at the RD. Methods: Fourteen pts were enrolled sequentially for AKR ppx and treated with orva-cel at the RD. The non-AKR ppx control group comprised the remainder of the phase 1 pts receiving orva-cel at the RD (n = 19). The median follow-up (range) was 3.0 mo (1.8–6.2) for the AKR ppx group and 8.8 mo (5.3–12.2) for the non-AKR ppx group. AKR was administered as 100 mg SC the night before orva-cel infusion, 3 h before the infusion (Day 1), and q24 h on Days 2–5. Dosing was increased to q12 h if CRS developed. CRS was graded by Lee (2014) criteria. Tocilizumab (T) and steroids (S) were used per protocol-specified treatment management guidelines. Results: Disease characteristics and outcomes are shown in the table. In AKR ppx and non-AKR ppx groups, median number of prior regimens was 6 and 5, and bridging Tx was used in 57% and 68% of pts, respectively. The total frequency of CRS was similar in the 2 groups, but with less G 2 in the AKR ppx pts; relative risk (95% CI) = 0.54 (0.21, 1.38). No G ≥3 CRS was seen in either group. The incidence of neurological events (NE), G ≥3 infection, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) was similar. T and S use was numerically lower with AKR ppx. Orva-cel expansion kinetics were similar in the 2 groups. All pts had a 2-month efficacy assessment, with ORR in 100% of AKR ppx and 95% of non–AKR ppx pts. Conclusions: In this nonrandomized evaluation of AKR ppx with orva-cel treatment, the incidence of G ≥2 CRS was lower in pts receiving AKR ppx. The use of AKR ppx produced no adverse effect on the incidence of NE, infection, or MAS/HLH, nor on orva-cel expansion or disease response. These results warrant further study of AKR ppx in CAR T cell therapy. Clinical trial information: NCT03430011. [Table: see text]
Preliminary analysis of a phase 1/2 study of NEXI-001 donor-derived multi-antigen-specific CD8+ T-cells for the treatment of relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT).
Authors: Al Malki Monzr , Vasu Sumithira , Modi Dipenkumar , Perales Miguel-Angel , Bui Donna , Edavana Vineetha , Kim Sojung , Suarez Lauren , Oelke Mathias , BednÃ¡rik Dan , Knight Robert D. , Varela Juan Carlos
Published: June 2021

2538

Background: Allogeneic HCT is a potentially curative therapy for many patients with AML that relies on a graft-versus-leukemia (GvL) effect. Patients who relapse after allogeneic HCT have a poor prognosis and few treatment options. Donor lymphocyte infusion (DLI) can achieve a GvL effect in some patients, however, efficacy is frequently associated with the development graft-versus-host disease (GVHD). There is a substantial need for treatment approaches that enhance the benefit of GVL while decoupling toxicities associated with GVHD. Methods: We report ongoing results from a first-in-human study (NCT04284228) of a non-genetically engineered, donor-derived adoptive cellular therapy product, NEXI-001, which contains multiple populations of CD8+ T cells that recognize different HLA 02.01-restricted peptides from the WT1, PRAME, and Cyclin A1 antigens. NEXI-001 contains T cell memory subtypes that combine anti-tumor potency with long-term persistence. Results: At the time of this analysis, 7 patients with relapsed AML after allogeneic HCT were enrolled. Five Patients were treated with single infusions of NEXI-001 at three different dose levels: 50, 100 and 200 million. Currently, the median follow-up is 5 months. Significantly, GVHD, cytokine release syndrome, neurotoxicity, or NEXI-001-related adverse events were not observed. NEXI-001 treatment resulted in reductions in red blood cell and platelet transfusions and increased donor chimerism. Decreases in myeloblasts in bone marrow and peripheral blood and reduction in the size of an extramedullary myeloid sarcoma were suggestive of an anti-leukemia effect (Table). Correlative studies indicate that NEXI-001 CD8+ cells undergo a rapid proliferation after infusion and are also associated with a robust hostlymphocyte recovery that occurs as quickly Day 3 after infusion. NEXI-001 infused CD8+T cells are detectable by multimer staining in peripheral blood of patients and proliferate over time. TCR sequencing analyses determined that infused NEXI-001 cells contain T cell clones that were undetectable in the peripheral blood of patients at baseline but were detected in blood and bone marrow and persist over time. Conclusions: NEXI-001 has the potential to enhance GvL effect without the associated toxicities of GVHD, cytokine release syndrome, and neurotoxicity. Due to these encouraging results, the trial will proceed with an evaluation of repeated NEXI-001 dosing Clinical trial information: NCT04284228. [Table: see text]
Assessment of cancer-specific microbiome signature of response to immune checkpoint inhibitors.
Authors: Sarfaty Michal , Desjardins Christopher A. , Giardina Paul , Bardhan Kankana , Pandian Swarna , Halley Keith , Halvorsen Elizabeth M. , Callahan Margaret K. , Postow Michael A. , Lee Chung-Han , Kotecha Ritesh , Kashani Daniel , Ratna Neha , Regazzi Ashley Marie , Henn Matthew R. , Hellmann Matthew D. , Iyer Gopa , Ford Christopher B. , Peled Jonathan U.
Published: June 2021

2574

Background: Clinical and preclinical experiments suggest that the gut microbiome can affect outcome in cancer patients treated with immune checkpoint inhibitors (ICI). Most data to date has been in melanoma, so the relationship of the gut microbiome with treatment outcome in other cancers is poorly understood. Here, we evaluated the microbiome composition in correlation to ICI response in patients with metastatic lung, urothelial, or renal cancer, as well as metastatic melanoma. Methods: Fecal microbiome samples were obtained from patients with metastatic melanoma, lung, urothelial, or renal cancer immediately before ICI therapy was initiated. Bacterial genomic DNA was isolated and profiled by whole metagenome sequencing. Sequence data were analyzed using a custom implementation of MetaPhlAn2. Response to ICI was defined as partial or complete response or remaining on therapy for more than 6 months. Results: Samples were prospectively collected from 94 patients, including metastatic melanoma (n = 17), lung (n = 44), urothelial (n = 23), or renal cancer (n = 10). Treatment included anti-PD(L)1 monotherapy (n = 51), anti-PD1 + anti-CTLA4 combination therapy (n = 17), or a combination of anti-PD1 and chemotherapy (n = 26). Clinical response was observed in 58% of patients, including partial or complete response (45%) and on treatment for more than 6 months (55%, with 31% on treatment for more than 1 year). Although the variance in the composition of pretreatment microbiome samples did not explain response alone (R vs NR, PERMANOVA, p = 0.273), a significant portion of the variance in microbiome composition was explained by the interaction of cancer type and outcome (PERMANOVA, p = 0.014), suggesting a cancer-specific microbiome relationship. Notably, there was some similarity in the signature of NR across three cancer types (lung, urothelial and melanoma). One sample in this NR cluster was from a patient whose metastatic NSCLC was nonresponsive to pembrolizumab and carboplatin/pemetrexed. This microbiome sample was evaluated in vivo using subcutaneous MC38 and CT26 tumor models in germ-free mice. In contrast to mice colonized with stool from a healthy donor, mice colonized with stool from this patient yielded a nonresponsive result upon treatment with anti-PD1 or anti-PD-L1 in combination with anti-CTLA4. Conclusions: Analysis of the fecal microbiome composition from patients with metastatic lung, urothelial, renal cancer, and melanoma identified a cancer-specific signature of R and NR to ICI. Across three cancer types, a consistent signature of NR was identified and corroborated experimentally in preclinical models.
CheckMate 8KX: Phase 1/2 multitumor preliminary analyses of a subcutaneous formulation of nivolumab (± rHuPH20).
Authors: Lonardi Sara , Lugowska Iwona , Jackson Christopher G. C. A. , O'Donnell Anne , Bahleda Rastilav , Garrido Marcelo , Latten-Jansen Loes , Chacon Matias , Yimer Habte Aragaw , Camacho Trixia , Konduri Srivani , Aras Urvi , Sanghavi Kinjal , Vezina Heather , Dolfi Sonia , Alessi Federica , Harvey R Donald , Trigo José , Calvo Aitana
Published: June 2021

2575

Background: Immunotherapy has transformed cancer survival expectations. Nivolumab (NIVO), a programmed death-1 inhibitor, is approved for intravenous (IV) administration across multiple cancers. BMS is developing a subcutaneous (SC) NIVO formulation with a permeation enhancer, recombinant human hyaluronidase PH20 enzyme (rHuPH20), to allow for more rapid delivery and the potential to decrease treatment burden. We report the first data on pharmacokinetics (PK), pharmacodynamics, safety, and immunogenicity for SC NIVO + rHuPH20. Methods: CheckMate 8KX is a phase 1/2 study in checkpoint inhibitor-naïve patients (pts) who were ≥ 18 years of age, ECOG PS 0–1, with metastatic/unresectable solid tumors and measurable disease. The primary objective was to describe SC NIVO PK; secondary objectives were safety and immunogenicity. Additional analyses compared exposures to historical IV NIVO (Zhao X, et al. J Clin Oncol 2020;31:302–309). In cycle 1, pts in Part A received SC NIVO 720 mg + rHuPH20, and pts in Part B received SC NIVO 720 mg, SC NIVO 960 mg + rHuPH20, or SC NIVO 960 mg. For cycles 2+, pts in Parts A and B received IV NIVO 480 mg every 4 weeks (Q4W). Pts still on study switched to Part C, SC NIVO 1200 mg + rHuPH20 until end of therapy. In Part D, pts received de novo SC NIVO 1200 mg + rHuPH20 Q4W. Results: Patient characteristics varied by age, weight, tumor type, and prior treatment. NIVO exposures increased with increasing SC dose (Table). For 960 mg and 1200 mg NIVO + rHuPH20, Cavg and Ctau were above geometric mean exposures for IV NIVO 3 mg/kg every 2 weeks (Q2W), and Cmax was below IV NIVO 10 mg/kg Q2W. In Part C (n = 28), 13 (46.4%) pts experienced any-grade TRAEs with no new/worsening grade 3+ TRAEs or TRAEs leading to discontinuation/death; 7 (25.0%) reported grade 1 local site reactions. In Part D (n = 36), 27 (75.0%) pts experienced any-grade TRAEs, 4 (11.1%) grade 3/4 TRAEs, 2 (5.6%) serious grade 3/4 TRAEs with 1 leading to discontinuation, and no treatment-related deaths; 10 (27.8%) reported grade 1 local site reactions. Anti-NIVO antibodies (Ab) were observed with SC NIVO but not associated with altered PK/safety, or neutralizing Ab. Exploratory biomarker data found increased CD8+ tumor-infiltrating lymphocytes and PD-L1 tumor expression in post-treatment biopsies, similar to IV NIVO. Conclusions: Exposures associated with SC NIVO + rHuPH20 doses investigated in CheckMate 8KX were well tolerated, with a safety profile consistent with IV NIVO. Data support evaluation of SC NIVO + rHuPH20 in a phase 3 study. Clinical trial information: NCT03656718. [Table: see text]
Phase I/II study of nivolumab plus vorolanib in patients with thoracic malignancies: Interim efficacy of the SCLC and primary refractory NSCLC cohorts, and safety data across all cohorts.
Authors: Wong Selina K. , Whisenant Jennifer G. , Bestvina Christine M. , Berry Lynne D , Owonikoko Taofeek K. , Sanborn Rachel E. , Lammers Philip Edward , El Osta Badi Edmond , Ramalingam Suresh S. , Carlisle Jennifer W , Steuer Conor Ernst , Borghaei Hossein , Selvaggi Giovanni , Shyr Yu , Wakelee Heather A. , Horn Leora , Beckermann Katy
Published: June 2021

2578

Background: Combination strategies to improve the efficacy of single agent immune checkpoint inhibitors (ICIs) are increasingly being explored, with one strategy being the addition of vascular endothelial growth factor (VEGF) inhibition. Having shown promise in the treatment of hepatocellular carcinoma and renal cell carcinoma, NCT03583086 is a multi-institutional, phase I/II study of combination vorolanib and nivolumab in both naïve and refractory thoracic tumors that progressed on at least one prior line of platinum-based chemotherapy. Though structurally similar to the tyrosine kinase inhibitor, sunitinib, vorolanib was designed to have a more favorable safety profile with comparable efficacy. Here we present safety data across all cohorts and interim efficacy analyses of the SCLC and NSCLC with primary resistance to ICI-based therapy cohorts, both of which have now completed enrolment. Methods: The maximum tolerated dose determined in phase I was vorolanib 200mg daily and nivolumab 240mg q2 weeks. Phase II uses a two-stage MinMax design across 5 cohorts with objective response rate (ORR) as the primary endpoint: NSCLC (ICI naïve, primary refractory, and acquired resistance), SCLC, and thymic carcinoma. Primary refractory is defined as radiographic progression of disease within 12 weeks of ICI initiation. Results: As of January 2021, 75 patients have been enrolled across all cohorts. Stage 1 of the SCLC and primary refractory NSCLC cohorts have completed accrual at 18 and 15 patients, respectively. In the SCLC cohort, disease-control rate (DCR) was 7% and no objective responses were achieved among 14 evaluable patients. In the primary refractory NSCLC cohort, DCR was 57% and ORR 7% (1 partial response) among 14 evaluable patients. A total of 140 treatment-related adverse events (TRAEs) have been reported, 13 (9%) were grade 3 and there were no grade 4/5 events. Fatigue (9%), nausea (6%), diarrhea (6%), ALT elevation (5%), and AST elevation (5%) were the most common all grade TRAEs. The most common grade 3 TRAEs were ALT elevation and hypertension. Conclusions: This therapeutic strategy of nivolumab plus vorolanib appears to be a well-tolerated combination with a manageable safety profile. Adding VEGF inhibition may offer additional disease control in the setting of NSCLC with primary resistance to ICIs, but neither the SCLC or primary refractory NSCLC cohorts achieved the pre-determined target number of objective responses for progression to stage 2 of the study. Enrolment in the other 3 cohorts as well as exploratory correlatives are ongoing. Clinical trial information: NCT03583086.
First-in-human, phase I study of PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in biochemical relapse (BCR) and metastatic castration-resistant prostate cancer (mCRPC).
Authors: Autio Karen A. , Higano Celestia S. , Nordquist Luke T. , Appleman Leonard Joseph , Zhang Tian , Zhu Xinhua , Babiker Hani M. , Vogelzang Nicholas J. , Prasad Sandip , Schweizer Michael Thomas , Billotte Stephane , Binder Joseph , Cavazos Nora , Li Ruifeng , Chan Kam , Cho Helen , Dermyer Michael , Hollingsworth Robert , Kern Kenneth Alan , Petrylak Daniel P.
Published: June 2021

2612

Background: Therapeutic vaccines targeting PC-associated antigens represent attractive approaches in combination with immune checkpoint inhibitors (ICI). Safety/antitumor activity of PF-06753512 (PrCa VBIR) was evaluated in a phase I, dose-escalation and expansion study in patients (pts) with BCR prior to ADT and in pts with mCRPC either prior to or after failure of novel hormone therapy. PrCa VBIR consists of: 1) priming immunization with a replication-deficient adenoviral vector (AdC68) expressing PSA, prostate-specific membrane antigen and prostate stem cell antigen; 2) boosts with plasmid DNA (pDNA) encoding the same antigens by IM electroporation; 3) ICI given subcutaneously, including anti CTLA-4 antibody tremelimumab (TRM) and anti PD-1 antibody sasanlimab (SSL). Methods: AdC68 ± ICI(s) were given on months (mos) 1 and 5 and pDNA ± ICI(s) on mos 2–4 and 6–8. After 8 mos, maintenance pDNA + ICI(s) were given every 1 or 2 mos. In Part A (6 escalation cohorts), pts with mCRPC received AdC68 (4 or 6x10e11 viral particles) + pDNA 5 mg ± ICIs (TRM alone 80 mg; TRM 40 or 80 mg + SSL 130 or 300 mg). In Part B (3 expansion cohorts), pts with mCRPC received AdC68 6x10e11 + pDNA 5 mg + TRM 80 mg + SSL 300 mg; pts with BCR received similar vector and pDNA + TRM 80 mg ± SSL 130 mg. Primary objectives: Assess overall safety (CTCAE v4.03), determine expansion dose. Secondary objectives: Anti-tumor activity (RECIST v1.1, Prostate Cancer Working Group 3, PSA 50 response) and immune response. (Note: Database remains open, some queries pending). Results: As of Sept 15, 2020, 91 pts were treated in dose-escalation (n=38) and expansion (n=53; BCR=35, mCRPC=18). Immune responses (ELISpot) were positive in some pts. Grade (G) 3 or 4 treatment-related adverse events (TRAEs) developed in 38.5% (35/91) of pts. G5 TRAEs occurred in 2 pts (n=1 G4 myasthenia gravis + G5 pulmonary embolism; n=1 G5 myocarditis). irAEs were more frequent in BCR compared to mCRPC. See the table for efficacy data. Conclusions: Vaccination with PrCa VBIR had a manageable safety profile. TRAEs increased when 2 ICIs were given. Some pts with BCR experienced durable PSA-50 responses without ADT; patients with mCRPC had few objective tumor responses, but had prolonged median rPFS. PrCa VBIR appears to stimulate antigen-specific immunity and results in noticeable antitumor activity, particularly in androgen sensitive disease. Clinical trial information: NCT02616185. [Table: see text]
Long-term follow up of patients with mesothelioma treated with dendritic cell therapy in three phase I trials.
Authors: Dumoulin Daphne W , Cornelissen Robin , Bezemer Koen , Baart Sara , Aerts Joachim
Published: June 2021

2618

Background: Immunotherapy targeting PD-(L)1 has become indispensable in the treatment of many malignant tumors. Recently, checkpoint inhibition using anti-PD-1 in combination with anti-CTLA-4 was proved to be effective in patients with malignant pleural mesothelioma (MPM). However, the minority of patients benefit from this treatment. The lack of immunotherapy efficacy in the majority of patients with mesothelioma can be explained by the fact that mesothelioma is a tumor with an “immune-desert” phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of dendritic cells (DCs), which were cultured, activated, and exposed to antigens ex-vivo, this “immune-desert” phenotype might be turned into an “inflamed” phenotype. Previously, we performed and published three phase I trials using activated DCs, which support this concept. Here, we report the long-term survival of the patients treated with DCs in these three phase 1 studies. Methods: We collected the survival data of the phase 1 trials using DC therapy in patients with MPM. In the first two trials, DCs loaded with autologous tumor lysate were used, while in the third allogeneic tumor lysate was used to load the DCs (Mesopher). Results: Between 2006 and 2015, in the three studies combined, 29 patients with MPM were treated with DC vaccination. At data cut-off, the median OS was 27 months (95% confidence interval (CI): 21 – 47 months). OS at 2 years was 55.2% (95% CI: 39.7%-76.6%), OS at 5 years was 20.7% (95% CI: 10.1%-42.2%). Conclusions: The long-term follow up of MPM patients treated with DC vaccination in the three separate phase 1 trials show a promising signal, with a 2-year OS of over 50% and a 5-year OS of over 20%. In addition, 2 patients are alive after 10 years of treatment. In our opinion, these findings show the potency of DC vaccination therapy in long-term activation of the immune system. DC vaccination therapy in patients with MPM is currently being investigated in a large, randomized phase II-III trial (NCT03610360) and in pancreatic cancer. Additional biomarker studies, as well as treatment combinations with for example ICI, could further improve the outcomes of DC-vaccination therapy. Clinical trial information: NCT02395679. [Table: see text]
A phase I clinical trial investigating the telomerase vaccine UV1 in combination with pembrolizumab in patients with advanced melanoma.
Authors: Zakharia Yousef , O'Day Steven , Rasch Wenche , Milhem Mohammed M.
Published: June 2021

2620

Background: UV1, a telomerase peptide-based vaccine, consists of 3 long peptides (15-30 aa) representing a 54 aa sequence in the catalytic unit of the reverse transcriptase subunit of telomerase (hTERT). UV1 contains both CD4 and CD8 epitopes, and immunogenicity is shown in 78% of HLA unselected patients (pts.) in prior studies. UV1 induced expansion of hTERT specific CD4+ T cells that might be relevant in tumors expressing telomerase, theoretically enabling enhanced checkpoint efficacy in pts. with insufficient spontaneously primed T cells. Reciprocally, checkpoint inhibitor may support the UV1-induced T cells and provide increased effector activity, as these cells may be restricted by intrinsic and tumor-induced suppressor mechanisms. Methods: UV1 was combined with standard of care pembrolizumab in pts. with advanced melanoma. The primary objective of this phase I, multicenter study (NCT03538314), was to evaluate safety and tolerability of UV1 in combination with standard pembrolizumab. Secondary objective was evaluation of response rate (RR) according to iRECIST. Pts. received, in a serial manner, adjuvant GM-CSF and UV1 (300μg) intradermally followed by pembrolizumab. The first 3 UV1/GM-CSF doses were given during week 1, and from week 2 in combination with pembrolizumab (Q3W). Two different doses of GM-CSF were investigated: 37.5μg (20 pts. cohort 1) and 75μg (10 pts. cohort 2). Totally 8 UV1/GM-CSF vaccinations per pt. were planned (14 weeks). Results: In total 30 pts. were enrolled; cohort 1 (N = 20); cohort 2 (N = 10). The abstract reports cohort 1 results. The majority of adverse events (AEs) reported was grade 1 or 2 (48%, 41%). Main AEs were fatigue (8%), injection site reaction (5%), diarrhea (4%) and pyrexia (3%). 18% and 30% of AEs were possibly/definitely related to UV1 or pembrolizumab, respectively. Three patients experienced SAE, one (inflammatory arthritis) was considered possibly related to UV1. No severe allergic reactions were observed. Pembrolizumab was continued after completion of UV1 treatment in 14 pts. for a mean of 8.2 months (range 3-21). Four pts. discontinued pembrolizumab due to PD, one for irAE and one for unknown reason. The RR was 60%, with 5 CRs, and the 1-year survival rate 85 %. Conclusions: Results from cohort 1 (N = 20) show that the treatment of UV1 together with pembrolizumab was safe and well tolerated in patients with advanced melanoma. Updated data with minimum 18 months follow-up will be presented at the conference. Cohort 2 results will be presented at a later stage. Clinical trial information: NCT03538314. [Table: see text]
Real-world outcomes of treatment with immune checkpoint inhibitors in unique patient cohorts: Elderly, non-caucasian race, poor performance status, obese, chronic viral infections, and autoimmune diseases.
Authors: Shah Neil J. , Wang Shuo , Williams Aquino , Weber Melinda , Sinclaire Brittany , Gourna Paleoudis Elli , Alaoui Adil , lev-Ari Shaked , Adams Shari , Kaufman Jordan , Parikh Sahil B. , Tonti Emily , Muller Eric , Serzan Michael T , Cheruku Divya , Ahn Jaeil , Pecora Andrew , Ip Andrew , Atkins Michael B.
Published: June 2021

2641

Background: Immune Checkpoint Inhibitors (ICI) have revolutionized current cancer treatment. Nevertheless, outcomes data across various patient cohorts are lacking. To address this knowledge gap, we conducted a comprehensive analysis of real-world data (RWD) that included patient cohorts traditionally underrepresented in clinical trials. Methods: We identified patients (pts) treated with ICI (anti-CTLA-4, anti-PD(L)1 or their combination at 6 US academic and community hospitals from 1/2011 – 4/2018. Clinical data obtained from EHR and CTCAE V4.03 was used to define immune-related adverse events (irAEs). Results: A total of 1332 pts treated with 1443 unique ICI treatments were included in the cohort. The median age was 66 (21-87), Male 58% (827), Caucasian 70% (1004), African American (AA) 16% (232), other race 14% (207), ECOG PS 0,1 79% (1130), chronic viral infection 5% [hepatitis B (24), hepatitis C (32) and HIV (17)], with BMI > 30 22% (287) and autoimmune disease (AID) 15% (215). Lung cancer (NSCLC) 34% (423), and melanoma 27% (389) were top 2 tumor types and nivolumab 38% (544), pembrolizumab 23% (332), and ipilimumab plus nivolumab 12% (180) were the most common ICI treatments. Overall survival (OS) was worse for patients with ECOG ≥2 (0.34 - 0.63) vs. ECOG 0,1 (1.27 - 1.73, P <0.001), and better with AID (1.21 - 2.63) vs. no AID ( 0.90 - 1.24, P=0.01) and Caucasian (1.02 - 1.45) vs AA (0.72 - 1.30, P=0.02). No difference in OS was noted for sex, other races, h/o chronic viral infection or obesity. We performed an analysis of OS and irAEs restricted to NSCLC patients (n=423); (N=447 unique ICI treatments); age >75 27% (120), AA 28% (124), Female 50% (224), ECOG PS ≥2 23% (104), BMI >30 15% (62), chronic viral infections 10% (44), and AID 14% (62). The ICI therapies were nivolumab 55% (245), pembrolizumab 23% (102), and atezolizumab 6% (27) and 16% (others). Data is contained in the table. Conclusions: Overall, in our RWD, OS appeared to be similar across above cohorts except poor OS for pts with ECOG ≥2. irAEs also appeared to be similar across cohorts except less with ECOG ≥2. In NSCLC cohort, we noted similar findings except less irAEs in Male cohort. Prospective studies are needed to confirm the above findings.[Table: see text]
Incidence of hepatitis associated with addition of immune checkpoint blockade to conventional solid tumor therapy: A meta-analysis of phase 3 randomized clinical trials.
Authors: Fujiwara Yu , Horita Nobuyuki , Namkoong Ho , Miyashita Hirotaka , Harrington Matthew , Galsky Matt D.
Published: June 2021

2645

Background: Immune checkpoint blockade (ICB) has emerged as a promising treatment strategy for many solid tumors. Although safe for many patients, ICB causes immune-related adverse events (irAEs) including hepatitis, which may result in morbidity and treatment disruption. Severe hepatitis requires immunosuppression, including corticosteroids and mycophenolate mofetil. We conducted a meta-analysis of clinical trials to investigate the effect of adding ICB to conventional solid tumor therapy on the incidence of hepatitis. Methods: Phase 3 randomized clinical trials (RCTs) comparing ICB and conventional therapy to conventional therapy alone were chosen by database search on PubMed, Embase, Web of Science, and Cochrane Library. The odds ratios [OR] of any-grade and grade ≥3 hepatitis, elevated aspartate aminotransferase (AST), and elevated alanine aminotransferase (ALT) were calculated. Meta-analysis was conducted to determine the incidence of hepatitis, elevated AST, and elevated ALT among patients receiving ICB and those receiving conventional therapy alone. Subgroup analysis based on the mechanism of ICB (Cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] inhibitor, programmed cell death protein 1 [PD-1] inhibitor, and programmed death-ligand 1 [PD-L1] inhibitor) was also conducted. Results: A total of 29 randomized controlled trials (RCTs) enrolling 18,829 participants were analyzed. Incidence of hepatitis was derived from 24 RCTs enrolling 15,183 patients, and incidence of grade ≥3 hepatitis was derived from 22 RCTs enrolling 13,846 patients. Incidence of elevated AST was extracted from 18 RCTs, and incidence of elevated ALT was extracted from 20 RCTs. Addition of ICB to conventional therapy was associated with an increase in incidence of any-grade hepatitis (OR 2.54, 95% confidence interval [CI] 1.82-3.55) and grade ≥3 hepatitis (OR 4.22, 95% CI 2.51-7.11). The addition of ICB was also associated with an increase in incidence of elevated AST (any grade: OR 2.19, 95% CI 1.59-3.03; grade ≥3: OR 3.18, 95% CI 1.85-5.48) and elevated ALT (any grade: OR 2.08, 95% CI 1.47-2.92; grade ≥3: OR 2.41, 95% CI 1.40-4.14). Subgroup analysis based on the mechanism of ICB demonstrated increased incidence of grade ≥3 hepatitis associated with CTLA-4 inhibitor, PD-1 inhibitor, and PD-L1 inhibitor therapy (OR 2.78, 95% CI 1.26-6.14; OR 6.30, 95% CI 2.23-17.78; OR 4.73, 95% CI 1.83-12.23, respectively). No significant difference of heterogeneity was observed among subgroups ( I2= 0%, p = 0.43). Conclusions: Addition of ICB to conventional solid tumor therapy was associated with increased incidence of any-grade and severe hepatitis, and elevations of AST and ALT, regardless of the mechanism of ICB. Clinicians should weigh the risk of liver toxicity when considering addition of ICB therapy in patients with solid tumors.
Circulating tumor DNA to investigate resistance mechanism and clone evolution of ALK TKI treated lung adenocarcinoma.
Authors: Hua Gang , Chen Xiaoxi , Yu Ruoying , Bao Hua , Wu Xue , Shao Yang
Published: June 2021

3011

Background: Sequential treatment with first-, second-generation ALK TKI followed by third-generation TKI (lorlatinib) have been widely applied to ALK-positive lung cancer. However, acquired resistance is often driven by secondary ALK mutations, which are needed to be further explored. Circulating tumor DNA, a non-invasive approach, can detect tumor-derived DNA from multiple metastatic sites and has become a promising strategy for assessing the genetic evolution of tumors and analyzing TKI resistance. Methods: Post-progression plasma specimens were collected and sequenced with a targeted gene panel from a total of 116 patients underwent ALK TKI treatment with from February 2014 to April 2020. The ALK TKIs administrated in this cohort included crizotinib (first-generation), ceritinib (second-generation), alectinib (second-generation), brigatinib (second-generation), ensartinib (second-generation) and lorlatinib (third-generation). Results: In this ALK-positive lung adenocarcinoma cohort, 49.1% were female and the rest were male with a median age of 52 (range 20 to 79). More than half of patients received more than one line of ALK TKI treatment. The most frequent ALK fusion type is EML4-ALK including EML4-ALK v1(E13; A20, 37/116, 31.9%) and EML4-ALKv3(E6a/b; A20, 49/116, 42.2%). TP53 (29.1%, 41/141) was the most frequently mutated gene other than ALK. Frequently identified secondary mutations in patients progressing on ALK inhibitors were ALK mutations L1196M and G1202R. ALK G1202R was more common in patient with v3 fusion than in v1 (25.8% vs 0%; P<.001) while ALK L1196M was more common in v1 than in v3 (20.8% vs 3.2%; P=.005). Meanwhile, G1202R was identified at higher ratio in patients progressed on second-generation ALK TKI than first- and third-generation ALK TKI (11.3% vs 0% and 9.1%) whereas L1196M was more found in patients progressed on first-generation ALK TKI (9.1% vs 1.9% and 4.5%). Other identified secondary mutations were ALK F1174C/V/L, E1210K/Q, D1269A, D1203N and L1122M/V. Compound ALK mutations (≥2 concurrent ALK mutations) were more common in patients relapsed on third-generation ALK TKI lorlatinib (36.4%) compared to first- (12.1%) and second-generation (20.8%) ALK TKIs. Using serial plasma specimens, clone evolution analysis showed that five patients developed compound ALK mutations after sequential ALK TKI treatments and two novel ALK compound lorlatinib-resistant mutations D1203N+I1171N and F1174C+G1202R were identified. Conclusions: Genotyping of sequential post-progression plasma specimens reveals that treatment with sequential first-, second-, and third-generation ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance.
A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose escalation results.
Authors: Tolcher Anthony W. , Carneiro Benedito A. , Dowlati Afshin , Abdul Razak Albiruni Ryan , Chae Young Kwang , Villella Jeannine A. , Coppola Sheryl , Englert Stefan , Phillips Andrew C. , Souers Andrew J. , Salman Zeena , Penugonda Sudhir , Powderly John D. , LoRusso Patricia
Published: June 2021

3015

Background: Mirzotamab clezutoclax (ABBV-155) is a first-in-class antibody drug conjugate comprised of a BCL-XL (B-cell lymphoma - extra long) inhibitor, solubilizing linker, and a monoclonal anti-B7H3 antibody. Methods: Patients (pts) with relapsed and/or refractory (R/R) solid tumors were administered mirzotamab clezutoclax with or without paclitaxel. Dose escalation of mirzotamab clezutoclax was guided by Bayesian continual reassessment. Primary outcomes were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary outcomes: safety, pharmacokinetics, and overall response rate per RECIST v1.1. Results: As of November 6, 2020, 31 pts received mirzotamab clezutoclax monotherapy (monoTx) and 28 pts received combination therapy with paclitaxel (comboTx). Overall demographics: median age 62 years (range 25–79); 61% female; 86% white; 24% ECOG 0, 76% ECOG 1; 51% had > 3 prior systemic therapies. The median duration of mirzotamab clezutoclax exposure was 3 cycles (range 1–14) for monoTx and 5 cycles (range 1–14) for comboTx. There were no dose limiting toxicities (DLT) reported with monoTx. In comboTx, 2 pts experienced a DLT: Grade 4 neutrophil count decreased and Grade 3 lymphocyte count decreased considered related to paclitaxel. 97% of all pts had adverse events (AEs). The most common AEs (in ≥20% of pts) overall were fatigue (39%), nausea (25%), diarrhea and arthralgia (22% each), vomiting and hypokalemia (20% each). AEs in ≥5 pts related to mirzotamab cleuzutoclax were fatigue (27%), diarrhea (12%), and nausea (9%). Related Grade 3/4 AEs overall (in > 1 patient) included anemia, lymphocyte count decreased, fatigue, and diarrhea (3% each). One patient on monoTx experienced a fatal cardiac arrest. No fatal AEs occurred on comboTx. Responses were observed with comboTx as shown in the Table. Conclusions: Mirzotamab clezutoclax as monotherapy and with paclitaxel demonstrates a tolerable safety profile (MTD not reached) with anti-tumor activity in R/R solid tumors. Further investigation in prospectively-selected B7H3 positive tumors as monoTx in pts with R/R small cell lung cancer and with paclitaxel in pts with R/R breast cancer and docetaxel in pts with R/R non-small cell lung cancer in the dose expansion phase is ongoing. Clinical trial information: NCT03595059. [Table: see text]
Multiomic, plasma-only ctDNA NGS assay for minimal residual disease (MRD) detection in solid tumors.
Authors: Kurata Jessica , Price Kristin Sedgwick , Banks Kimberly , Zotenko Elena , Hite Dustin , Cheng Donavan , Parsana Princy , Ju Jin Hyun , Dinman Tara , Miao Zong , Talasaz AmirAli
Published: June 2021

3045

Background: Detection of minimal residual disease (MRD) by circulating tumor DNA (ctDNA) post-curative intent treatment is predictive of recurrence in many solid tumors. Due to biological challenges with low ctDNA shed in early-stage disease and potential to detect non-tumor derived alterations in plasma (e.g. CHIP), most ctDNA MRD assays are dependent on a priori knowledge of genomic alterations from tumor tissue to achieve high sensitivity and specificity. Tissue-dependent methods limit the clinical application of a MRD assay, especially in cancer types where tissue biopsy is challenging, neoadjuvant therapy (NAT) is standard of care, and/or rapid turnaround times are needed for clinical decision making. We previously validated an assay (Guardant Reveal) that combines somatic and epigenomic analysis to detect ctDNA from early-stage colorectal tumors without tumor tissue or peripheral blood cells. Here we describe the expansion of this assay to detect MRD across multiple tumor types. Methods: Cell-free DNA (cfDNA) fragments are extracted from patient plasma, partitioned based on methylation fraction, enriched using a panel to target informative genomic and epigenomic regions, barcoded, and pooled for sequencing. Methylation status is determined non-destructively and with minimal loss of molecules, allowing sensitive genomic and epigenomic analysis of the same cfDNA fragments. A single assay with a total panel size of 5.3 Mb was developed for MRD analysis in multiple cancer types, including CRC, Lung and Bladder. A “ctDNA detected” result is defined by the de novo identification of tumor-derived somatic variants and/or the observation of a tumor-specific methylation profile exceeding predefined thresholds. Results: The assay performance was tested using 163 pre-treatment clinical samples from patients with early-stage non small cell lung cancer (NSCLC) and bladder cancer and 133 self-declared healthy donors. Sensitivity for pre-treatment detection in NSCLC was 68.9% at 95% specificity (20/42 Stage I: 47.6%, 25/30 Stage II: 83.3%, 19/21 Stage III: 90.5%). Sensitivity for bladder cancer was 44.2% at 95% specificity (13/43 NMIBC: 30.2%, 18/27 MIBC: 66.7%). Additional development from larger cohorts and other tumor types is ongoing and data will be presented as available. Conclusions: Using cancer-specific genomic and epigenomic signals combined with learning-based classifiers, we developed a highly specific method for detecting the presence of ctDNA in early-stage NSCLC and bladder cancer patients from plasma without the need for tumor tissue but with comparable sensitivities to tissue-dependent approaches. A plasma-only MRD assay will allow for greater clinical impact by overcoming the challenges of tissue procurement, particularly following NAT, and enabling faster time to results.
Feasibility and clinical utility of cancer whole genome and transcriptome sequencing for pediatric and young adult solid tumors.
Authors: Shukla Neerav , Levine Max , Gundem Gunes , Spitzer Barbara , Gutierrez-Abril Jesus , Bouvier Nancy , Arango Ossa Juan E. , Medina-Martinez Juan , Stockfisch Emily , O'Donohue Tara , Zehir Ahmet , Viale Agnes , Modak Shakeel , Dela Cruz Filemon S. , Slotkin Emily K , Karajannis Matthias A. , Glade Bender Julia Lynne , Walsh Michael Francis , Kung Andrew , Papaemmanuil Elli
Published: June 2021

3063

Background: Next generation sequencing (NGS) assays have accelerated the identification of mutations and potential matched targeted therapies for patients with cancer. However, a significant proportion of patients do not derive clinical benefit from targeted panel sequencing approaches. Cancer whole genome and transcriptome sequencing (cWGTS) offers the opportunity to fully characterize tumors, but are challenged by significant cost and computational resource requirements, concerns of assay sensitivity, and the need to deliver curated results within clinically relevant time frames. We performed a prospective study to evaluate the feasibility and utility of cWGTS in pediatric and young adults with solid tumors. Methods: We developed an automated analytical workflow (Isabl) for the QC and processing of cWGTS data to include ensembl variant calling for germline and somatic substitutions, indels, and structural variants; fusion genes; gene expression; and mutation signatures. Treatment biomarkers were annotated using OncoKB with generation of a clinical prototype report. We tested the feasibility of cWGTS implementation, evaluated its analytical validity compared to standard diagnostic assays, and characterized the clinical utility of incremental findings in a prospective study of children and young adults treated at Memorial Sloan Kettering Cancer Center. Results: A total of 114 patients were enrolled. Standard NGS assays (MSK-IMPACT, MSK-Fusion) identified clinically relevant biomarkers in 22% of cases. The cWGTS process was completed, from sample acquisition to summary report, in less than 12 days. Comparison against clinically reported NGS results demonstrated high precision and recall for reported mutations (98.8%) with high concordance across variant allele representations (r2> 0.73). cWGTS identified additional oncogenic mutations not captured by targeted sequencing in 49% of patients. Furthermore, incremental findings, beyond those identified by NGS assays, of direct clinical relevance (diagnostic, prognostic, therapy guiding) were identified in 26% of patients. Importantly, < 5% of the incremental findings would have been captured by whole exome or transcriptome sequencing alone. Of possible therapeutic relevance, cWGTS analyses revealed a significantly higher tumor mutation burden than previously reported (range: 0 - 11.23). Conclusions: We demonstrate feasibility, analytical validity and clinical utility of cWGTS approaches in pediatric and young adult cancer patients, with nearly half of all patients having incremental findings that were not captured by standard targeted NGS approaches.
Validation of FAPi PET biodistribution by immunohistochemistry in patients with solid cancers: A prospective exploratory study.
Authors: Mona Christine , Benz Matthias R. , Hikmat Firas , Grogan Tristan , Lueckerath Katharina , Razmaria Ali A , Riahi Rana , Slavik Roger , Grigis Mark D , Carlucci Giuseppe , Kelly Kimberly A , Czernin Johannes , Dawson David D , Calais Jeremie
Published: June 2021

3066

Background: Fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts (CAF), a major component of tumor stroma, confer treatment resistance, promote local progression, metastasis and immunosuppression. Because FAP is selectively expressed in the tumor stroma of many cancers, radiolabeled small molecule ligands targeting FAP are being explored for their use as pan-cancer theranostic agents. The objective was to establish the spectrum of FAP expression across various cancers by immunohistochemistry (IHC) and to explore whether 68Ga-FAPi-46 PET image biodistribution faithfully reflects tumor FAP expression from resected tumor and non-tumor specimens. Methods: This study was a prospective, exploratory, imaging trial in cancer patients. Referred volunteer patients scheduled to undergo surgical resection of the primary tumor and/or metastases were eligible. Patients underwent one whole body 68Ga-FAPi-46 PET/CT scan. Subsequently, patients underwent surgical resection of the primary tumor and/or metastasis. The outcome measure was the correlation of 68Ga-FAPi-46 PET maximum standardized uptake value (SUVmax) with FAP IHC score in patient-matched cancer and non-cancer tissue. Results: The frequency of FAP expression across 14 cancers on tissue microarrays ranged from 25 to 100% (mean 76.6±25.3%). For imaging and IHC correlation, fifteen patients with the following cancer types were prospectively included: colorectal (n = 4), head and neck (n = 3), pancreas (n = 2), breast (n = 2),stomach (n = 1), esophagus (n = 2) and uterus (n = 1). All 15 patients underwent surgery following their 68Ga-FAPi-46 PET scan within a mean time interval of 16.1±14.4 days (range 1 – 50 days). For two patients the tumor was deemed unresectable. 68Ga-FAPi-46 SUVmax and IHC scores were higher in cancer tissue than in normal tissue: mean 68Ga-FAPi-46 SUVmax 7.4±4.6 (range 1.5-15.9) vs 1.6±1.2 (range 0.4-5.1), (p < 0.001) and mean FAP IHC score 2.38±0.65 vs 0.54±0.66 (p < 0.001), respectively. The FAP IHC scores strongly correlated with 68Ga-FAPi-46 SUVmax (p = 0.001, repeated measures correlation r = 0.85 (95% CI 0.53-0.95), p < 0.001). Conclusions: 68Ga-FAPi-46 PET biodistribution across multiple cancers strongly correlates with FAP tissue expression as measured by IHC. This translational validation paves the way for large scale prospective trials on the use of 68Ga-FAPi-46 PET/CT as a biomarker and stratification tool for FAP-targeted therapies. Clinical trial information: NCT04147494.
First-in-human phase I study of the bifunctional EGFR/TGFβ fusion protein BCA101 in patients with EGFR-driven advanced solid cancers.
Authors: Janku Filip , Hanna Glenn J. , Carvajal Richard D. , Paik Paul K. , Hernando-Calvo Alberto , Gillison Maura L. , Fu Siqing , Wheler Jennifer J. , Bohr David , Reiners Ralf , Tan Seng-Lai , Bilic Sanela , Bedard Philippe L.
Published: June 2021

3074

Background: Therapeutic targeting of EGFR has demonstrated efficacy in common advanced malignancies such as colorectal cancer (CRC), squamous cell of the head and neck (SCCHN), and non-small cell lung cancer (NSCLC). TGFβ has pro-tumorigenic effects on migration, invasion and tumor-specific immunosuppression, which may enhance the oncogenic effects of activated EGFR. Inhibition of EGFR signaling can lead to TGFβ upregulation as a resistance mechanism. BCA101 is a bifunctional recombinant fusion protein consisting of a chimeric anti-EGFR antibody and an extracellular domain (ECD) of human TGFβRII which demonstrated anti-tumor activity in several preclinical models. Methods: Patients with EGFR-driven advanced solid cancers refractory to standard therapies received BCA101 at escalating doses from 64 mg to 1000 mg intravenously (IV) weekly across 6 dose levels using a 3+3 design to determine dose limiting toxicities (DLT, established within 21 days of initial dosing), maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary endpoints include detailed pharmacokinetic (PK), pharmacodynamic (PD) studies in serial tumor and/or blood samples and assessment of anti-tumor activity. Results: As of 2/11/2021, 21 patients received single agent BCA101 at 64 (n = 3), 240 (n = 7), 500 (n = 2), 750 (n = 3), 800 (n = 3) or 1000 (n = 3) mg IV weekly, including patients with CRC (n = 6), SCCHN (n = 5) uveal melanoma (n = 2), ovarian cancer (n = 2), glioblastoma multiforme (n = 2), conjunctival melanoma, chordoma, pancreatic cancer and anal squamous cell carcinoma (all n = 1). These patients had 1-7 prior lines of antineoplastic therapy (median 4), including 3 patients with prior EGFR inhibitor exposure. Adverse events (AE) related to BCA101 observed in > 1 patient included grade (G) 1-2 rash (n = 9), G 1-2 lipase elevation (n = 2). G3 vitreous hemorrhage at the 240 mg dose level has been the only DLT. The MTD has not been reached and the RD will be based on safety, exposure and pending PD data. Saturation of the clearance was observed at doses above 500mg. Dose proportional increase in Cmax and AUC were observed with doses of 750-1000mg. Best RECISTv1.1 response was stable disease (SD) in 3/10 evaluable patients, with 1 patient on drug ≥4 months. Conclusions: BCA101 is well tolerated at biologically active doses. BCA101 is now being tested in combination with the PD-1 antibody pembrolizumab in patients with SCCHN and anal carcinoma. Clinical trial information: NCT04429542.