CAR T THERAPY TARGETED TO CLAUDIN18.2 SHOWS PROMISE IN SOLID CANCERS
Abstract 2509: Phase I trial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma
On behalf of Dr. Xianbao Zhan (Changhai Hospital, Shanghai, China), Dr. Jie Li presented findings from a first-in-human study of a Claudin18.2-specific CAR-T construct in gastric and pancreatic cancers. Claudin18.2 is a gastric-specific isoform of Claudin-18. After lymphodepletion, 7 gastric and 5 pancreatic cancer patients received 1-5 cycles of CAR-positive T cells, for a total of 0.5-55 x 108 CAR cells. Primary endpoints included safety, tolerability, and pharmacokinetics, and secondary measures such as PFS and ORR were investigated as well.
No serious adverse events were reported in this study, and all cytokine release syndromes were of grade 1-2. The total objective response rate was 33.3%, comprising 1 CR, 3 PRs, 5 SD, and 2 PD. The estimated median PFS was 136 days and the median OS was 242 days, warranting further investigation of this CAR construct in solid tumors.
ENCOURAGING RESPONSES TO BISPECIFIC ANTI-CD19/CD20 CAR T THERAPY IN NON-HODGKIN LYMPHOMA
Abstract 2510: Results of a phase I study of bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) modified T cells for relapsed, refractory, non-Hodgkin lymphoma
A phase I study of a CD19/CD20-targeted CAR T therapy was presented by Dr. Nirav Niranjan Shah (Medical College of Wisconsin, Milwaukee, WI). Patients with R/R B-cell non-Hodgkin lymphoma were treated with 2.5 x 105 – 2.5 x 106 41BB/CD3z LV20.19CAR T cells after lymphodepletion in this escalation/expansion trial, and monitored for dose-limiting toxicities. A secondary goal was to evaluate the feasibility of a local manufacturing process for the cellular therapy.
To date, fifteen patients were enrolled, with 3 patients each receiving 2.5 x 105, 7.5 x105, and 2.5 x 106 cells in the escalation phase, with no evidence of DLTs. The highest dose was then selected for the expansion phase, which has accrued six patients. Grade 1-2 CRS was developed by 11 patients, and grade 1-2 neurotoxicity in 3 patients; similarly, two patients developed grade 3 neurotoxicity, but ICU care was not required in any instance. At 28 days, the ORR was 82%, with 11 CR and 3 PR. All of the CR patients remained in remission throughout follow-up, some for over a year. In those patients that experienced progression, biopsy results indicated that they retained CD19 and/or CD20 positivity, meaning down-regulation of antigens was not a means of escape.
DIFFERENCES IN ACTIVITY OF COMBINATION CHECKPOINT IMMUNOTHERAPY IN ASYMPTOMATIC/SYMPTOMATIC MELANOMA BRAIN METASTASES
Abstract 9501: Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204)
Treatment of melanoma brain metastases with combination immune checkpoint blockade was presented by Dr. Hussein Abdul-Hassan Tawbi (MD Anderson Cancer Center, Houston, TX). The authors investigated a regimen of nivo 1 mg/kg + ipi 3 mg/kg Q3W x 4 followed by nivo 3 mg/kg Q2W in two cohorts of melanoma patients with brain metastases: those without symptoms or steroid treatment, and those with symptoms, regardless of steroid use. The study was evaluated in terms of the intracranial benefit rate (CBR = CR + PR + SD at equal to or greater than 6 mo).
101 patients were in the asymptomatic cohort, while 18 patients had symptomatic brain metastases. For those without symptoms, the CBR was 58.4%, with 29 CR and 26 PR. In the challenging symptomatic cohort, patients received a median of 1 dose of the nivo/ipi combination, and four patients entered the maintenance phase, resulting in a CBR of 22.2%. Over half of the patients in each cohort experienced a grade 3 or 4 adverse event, at 54.5% in the asymptomatic and 55.6% in the symptomatic cohorts. The results in the asymptomatic patients were encouraging, while symptomatic patients warrant further investigation.
CD19-TARGETED CAR T CELLS SHOW POTENTIAL IN HEAVILY PRE-TREATED CLL/SLL PATIENTS
Abstract 7501: TRANSCEND CLL 004: Minimal residual disease (MRD) negative responses after lisocabtagene maraleucel (Liso-Cel; JCAR017), a CD19-directed CAR T cell product, in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)
R/R chronic lymphocytic leukemia or small lymphocytic lymphoma patients were treated with a CD19-targeted CAR T cell therapy in a study presented by Dr. Tanya Siddiqi (City of Hope National Medical Center, Duarte, CA). Lisocabtagene maraleucel (liso-cel) was administered to patients with at least 2 previous lines of therapy at a dose of either 50 x 106 (9 patients) or 100 x 106 (14 patients) CAR+ cells, and dose-limiting toxicities and MRD were monitored.
At data cutoff, 23 patients with a median of 5 previous therapies had been treated with liso-cel. Grade 4 hypertension (N=1) and grade 3 CRS (N=2) were observed, while 3 patients had grade 3 neurological events and 3 instances of tumor lysis syndrome; otherwise, the most frequent grade 3/4 TRAEs were cytopenias. In the 22 evaluable patients, the best ORR was 81.8%, with 10 CRs. By day 30, 75% of patients had undetectable MRD in blood and 65% also in the bone marrow. At 6 months, the ORR was 67%, and uMRD was 64%. This study thus indicated promising responses in heavily pre-treated CLL/SLL patients.
CONFIRMATION OF ATEZOLIZUMAB BENEFIT IN PD-L1+ MTNBC
Abstract 1003: IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC)
The 2nd interim analysis of OS was presented by Dr. Peter Schmid (Queen Mary University of London, London, United Kingdom) for atezolizumab + nab-paclitaxel in mTNBC. In this study, patients were randomized to either atezolizumab 840 mg or placebo on D1 and D15 and nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 of the 28-day cycle until progression. Co-primary endpoints of the investigation included PFS in ITT and PD-L1+ patients, and OS in the same populations as well.
The results of this 2nd analysis were consistent with the previously-reported 1st analysis. PFS was significantly extended in the IO-treated group in both the ITT and PD-L1+ populations, with HRs of 0.8 (p=0.002) in the ITT and 0.62 (p<0.001) in the PD-L1 positive subgroup. No statistical difference was found in the OS for the ITT population between atezolizumab or placebo treatment (21.0 vs 18.7 mo); however, while not statistically tested in the PD-L1+ population, a 7-mo OS improvement was noted (25.0 vs 18.0 mo). The safety profile was similar to that reported in the first interim analysis. Therefore, this study re-emphasized the potential of 1st-line atezolizumab treatments in PD-L1-positive mTNBC.