Safety and Tolerability of Letetresgene Autoleucel (GSK3377794): Pilot Studies in Patients with Advanced Non-Small Cell Lung Cancer

Abstract

Purpose: The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A*02-positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06) patients with NY-ESO-1- and/or LAGE-1a-positive non-small cell lung cancer.

Patients and methods: Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent non-small cell lung cancer.

Results: More than 2,500 patients were screened for target expression. In the multiarm study, 738 (45%) of 1,638 tested patients were HLA-A*02-positive. NY-ESO-1 and LAGE-1a testing was positive in 12% (62/525) and 4% (15/348) of tested patients, respectively. Forty-one patients positive for HLA-A*02 and antigen expression were screened in the single-arm study. Overall, 43 patients underwent leukapheresis and 18 received lete-cel across studies. Lete-cel demonstrated a manageable safety profile. No fatal treatment-related serious adverse events (AE) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not seem to increase toxicity over lete-cel alone. Limited antitumor activity was observed; one of 18 patients had a durable response persisting for 18 months. Pharmacokinetic data showed similar T-cell expansion in all patients.

Conclusions: Extensive HLA-A*02 and antigen expression testing was performed to identify potential participants. Lete-cel was generally well tolerated and had no unexpected AEs. Antitumor activity was observed in a limited number of patients.

Figure 1.

Patient attrition and NY-ESO-1 and LAGE-1a expression profiles in the multiarm study. A, Patient attrition for multiarm study. A total of 1,698 patients in the multiarm study were screened and signed the informed consent form. Out of 13 dosed patients, six withdrew prior to meeting interventional phase completion criteria, per protocol. B, NY-ESO-1 IHC P-score distribution of screened NY-ESO-1–positive patients in the multiarm study. NY-ESO-1–positive protein expression was detected as a continuous variable with distribution between 10% and 100% expression. There were 62 patients whose tumors expressed NY-ESO-1 with a P score of ≥10%, 1+, 2+, and 3+, with each vertical bar representing a unique tumor sample depicted by contributing IHC intensity of 0+ in blue, 1+ in light blue, 2+ in light orange, and 3+ in orange (425 patients whose tumors expressed NY-ESO-1 <10%, 1+, 2+, and 3+ are not displayed). One patient (ID #61 in the figure) had two samples. C, NY-ESO-1 expression profile of dosed NY-ESO-1–positive patients in the multiarm study. The mITT population based on NY-ESO-1 IHC expression is individually represented in the vertical bars with the P-score broken down by contributing IHC intensity of 0+ in blue, 1+ in light blue, 2+ in light orange, and 3+ in orange. The patients are ordered by P score, which is indicated by the red line. NY-ESO-1–negative, LAGE-1a–positive patients in the mITT population not shown. D, LAGE-1a RNA expression distribution of all tested patients in the multiarm study. The plot of patients tested for LAGE-1a RT-PCR RNA expression, in which the red line indicates the cutoff = 4 ΔCT, with positive cases depicted in red and negative cases depicted in blue. Triangles represent all patients screened. The two patients dosed who were LAGE-1a–positive are distinguished in the figure with a red circle. Patients with “no expression” were imputed as having the lowest observable value divided by 3. The vertical axis is reversed (zero is higher); lower LAGE-1a score measured by RT-PCR represents higher expression levels. E, NY-ESO-1 and LAGE-1a prevalence. This is a bar chart displaying NY-ESO-1 and LAGE-1a prevalence. LAGE-1a testing was performed on tissue samples in reflex to NY-ESO-1–negative status for when tissue was available. Prevalence includes unique samples from the same patient. NE, not evaluable.

Figure 2.

Patient tumor responses in the single- and multiarm studies. A, Best overall response in the single- and multiarm studies (confirmed). In the single-arm study, data following first infusion only. One patient did not have measurable target lesions at baseline and does not appear in this plot; one patient received a transduced cell dose below the required dose level, per protocol, due to waiver granted. In the multiarm study, *arm A: one patient (M65) had unconfirmed PR. **Arm C: one patient (M1) had unequivocal progression due to new lesion and one patient died prior to first post-treatment scan and does not appear in this plot. B, Percent change from baseline in target lesion diameter in the multiarm study. Arm A patients are shown at left, and arm C is shown at right. Red circles indicate new target lesions. C, Median PFS and OS for each study. D, Radiographic images of case study patient S5, single-arm study. One patient from the single-arm study (S5) received two separate infusions, achieving best overall responses of confirmed PR from first infusion and SD from the second, per RECIST 1.1. The top left image is baseline before the first infusion, and top right is after 9 months. The bottom left image is baseline before the second infusion, and the bottom right is at week 11 after second infusion. E, Peak persistence and tumor shrinkage of case study patient S5, single-arm study. CR, complete response; LLOD, lower limit of detection; NA, not available; NE, not evaluable; PD, progressive disease; SD, stable disease.

Figure 3.

Cellular kinetics profile by patient in the single- and multiarm studies. A, Single-arm study. Cellular kinetics profile at first infusion by patient and responder status truncated at 12 weeks (available data), mITT population. B, Multiarm study. Cellular kinetics profile by patient and treatment arm truncated at 6 months (first infusion), mITT population. AUC_{0–28 days,} AUC from 0 to 28 days.