Vaccine may restore NSCLC response to checkpoint inhibitors
SAN FRANCISCO – An experimental allogeneic cellular vaccine combined with the checkpoint inhibitor nivolumab (Opdivo) may boost the immune response in patients with previously treated non–small cell lung cancer (NSCLC) tumors, results of a small phase 1b trial suggest.
Among 42 patients with NSCLC with no prior exposure to checkpoint inhibitors, the objective response rate (ORR) to the combination of nivolumab with the vaccine, dubbed viagenpumatucel-L (HS-110), was 21.4%, and among 20 patients with prior checkpoint inhibitor exposure the ORR was 15%, reported Daniel Morgensztern. MD, from Washington University in St. Louis and his colleagues.
“Preliminary results suggest that HS-110 plus nivolumab may induce CD8-positive T-cell infiltration in tumors that were considered ‘cold’ previously,” he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.
HS-110 is a therapeutic vaccine derived from a human lung adenocarcinoma cell line. The vaccine contains a broad range of tumor antigens that have been demonstrated to be present in a large proportion of patients with NSCLC. The cells are transfected with the gp96-Ig fusion protein which causes the cells to secrete the heat shock protein gp96. This protein “acts as a chaperone and adjuvant to induce cellular immune responses to various tumor antigens expressed by the host cell,” Dr. Morgensztern and his colleagues explained in a poster accompanying his oral presentation.
Daniel Morgensztern, MD
The rationale for the combination is that therapeutic cancer vaccines can stimulate increase in tumor-specific T cells, which is one of the primary mechanisms of action of immune checkpoint inhibitors.
The trial, nicknamed “Durga” for reasons that are not immediately apparent or explained by the investigators, is a multicohort study looking at the combination of HS-110 and immune checkpoint inhibitors. Dr. Morgensztern reported here on two initial cohorts with the combination of HS-110 and nivolumab. A second arm of the trial is examining the combination of HS-110 with pembrolizumab (Keytruda) with or without pemetrexed.
The phase 1b portion of the trial has been completed, and the phase 2 portion is ongoing.
Patients with previously treated NSCLC receive 1 × 107 HS-110 cells weekly for the first 18 weeks and nivolumab 3 mg/kg or 240 mg every 2 weeks until intolerable toxicity or tumor progression.
Cohort A included patients with no prior checkpoint inhibitor exposure, and cohort B is continuing to enroll patients who previously received a checkpoint inhibitor. The primary endpoint for cohort A was safety, and for cohort B the endpoint will be ORR.
Tissues were tested at baseline for programmed death-ligand 1 (PD-L1) expression on either 1% or greater or less than 1% of tumor cells, as well as for tumor-infiltrating lymphocytes (TILs). TIL-high tumors were defined as those with more than 10% CD8+ lymphocytes in the tumor stroma.
Cohort A included 44 patients, 42 of whom were available for the efficacy analysis as of the data cutoff in September 2018. As noted, the ORR in this cohort was 21.4%, consisting entirely of partial responses (PR). In addition, 29% of patients had stable disease, 40% had disease progression, and 10% were not evaluable. After a median follow-up of 14.4 months, the median overall survival (OS) had not been reached, with 60% of patients still alive.
Although the numbers were small, patients with low levels of CD8+ TILs appeared to derive the most benefit, with a 75% 12-month (OS) versus 50% for patients with TIL-high tumors. The 12-month OS rate among patients with less than 1% PD-L1 expression was 44% versus 54% for patients with 1% or greater PD-L1 expression.
The median progression-free survival (PFS) in cohort A was 2.6 months.
An analysis of enzyme-linked immune absorbent spot (ELISpot) assay results, which represent interferon-gamma secretion from T cells after stimulation with HS-110, showed a trend toward better OS among patients with absolute increases above the group median.
In addition, the investigators found that patients who had injection-site reactions had significantly better overall survival than patients who did not, with a hazard ratio of 0.15 (P = .0001).
Data on 20 out of a planned 40 patients in cohort B showed an ORR of 15%, which consists entirely of three PR, as well as a 40% stable disease rate (eight patients), 35% progressive disease (seven patients), and 10% not evaluable (two patients).
The most common grade 3 or greater treatment-related adverse events in cohort A included two fatal events, one from acute myocardial infarction and the other from a pulmonary embolism. Other serious but not fatal events included hyponatremia in three patients, and atrial fibrillation, congestive heart failure, appendicitis, seizure, rash, and hyperglycemia in one patient each.
In cohort B, two patients experienced hyponatremia, one had cardiac tamponade, and one had anemia.
The invited discussant Siwen Hu-Lieskovan, MD, PhD, from the Huntsman Cancer Institute at the University of Utah in Salt Lake City noted that two treatment-related fatalities in a small cohort was concerning and warrants further investigation.
The study is sponsored by Heat Biologics. Dr. Morgensztern disclosed a consulting/advisory role and research funding from the company and others. Two coauthors disclosed employment by and stock ownership in Heat Biologics. Dr. Hu-Lieskovan disclosed consulting for Amgen, Genmab, and Merck and institutional research funding from various companies.
SOURCE: Morgensztern D et al. ASCO-SITC 2019, Abstract 101.
Siwen Hu-Lieskovan, MD, PhD
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