FDA Approves Selpercatinib for RET+ Lung and Thyroid Cancers
May 09, 2020 03:20pm
By Lisa Astor
"Targeting PD-1/PD-L1 may provide a much-needed treatment option for patients with PDL1–positive advanced ATC."
Spartalizumab exhibited encouraging clinical activity and a satisfactory safety profile as monotherapy in patients with anaplastic thyroid carcinoma (ATC), according to results from a phase I/II study of patients with advanced solid tumors, which is the only know clinical trial to show responses to PD-1 inhibition in this patient population.
Results from the study were published in the Journal of Clinical Oncology.
Forty-two patients with ATC were enrolled and overall, ATC was confirmed by central pathology review in 38 patients (90%), whereas the remaining 2 patients with available tissue were diagnosed with high-grade malignant neoplasms with chondroblastic differentiation and Hürthle cell carcinoma.
The study treatment was administered for a median duration of 8 weeks (range, 1.7-113.6), which was as expected considering the aggressiveness of the disease. However, 11 patients (26%) received treatment for at least 50 weeks. During the course of treatment, 24 patients discontinued due to progressive disease, and 1 patient discontinued due to an adverse event (AE) that was unrelated to spartalizumab. Eight patients died during the study.
Responses were assessed both by RECIST v1.1 and immune-related response criteria (irRC). Eight patients achieved an objective response for an overall response rate (ORR) of 19% (95% CI, 8.6%-34.1%) by RECIST v1.1, which included complete responses (CRs) in 7% of patients and partial responses (PRs) in 12% of patients. By irRC, the ORR was 24% (95% CI, 12.1%-39.5%). Responses were ongoing at the time of data cutoff and ranged from 16.7 weeks to 1.6 years, with the median duration of response (DOR) not yet reached. Six patients were continuing treatment with ongoing responses at the time of data cutoff.
Postbaseline tumor size reduction was evaluated in 31 patients. Compared with baseline measurements, 13 patients showed some reduction.
The median progression-free survival (PFS) was 1.7 months by RECIST v1.1 (95% CI, 1.2-1.9) as well as by irRC (95% CI, 1.2-2.0 months). The PFS rate by RECIST v1.1 criteria was 17% and was 22% per irRC, at 1 year. Forty percent of the study population was alive at 1 year with a median overall survival (OS) of 5.9 months (95% CI, 2.4-not reached [NR]).
Through biomarker analyses, the investigators were able to characterize gene expression, tumor mutational burden (TMB), and mutations that affect cancer-related genes. The genes included in these analyses were TP53, TERT, BRAF, PTEN, and CDKN2A/B. A total of 27 patients were evaluable for the tumor mutational burden (TMB) assessment, and the median TMB was 3.78 mutations/Megabase (mut/Mb; range, 0-13.87).
TMB analyses were executed for 6 out of 10 responders and only 2 of them had a TMB greater than 5 mut/Mb. There was 1 patient who had a response to spartalizumab who was microsatellite stable who showed a TMB of 14 mut/Mb. This was the highest TMB in the ATC cohort of the study. Notably, the patient had a frameshift mutation in the DNA mismatch repair gene MSH6, which is a contributor to tumor genomic instability. In the remaining 5 patients who responded to treatment with spartalizumab and underwent mutational testing, no mutations were identified that would have impacted mismatch repair proteins.
In terms of PD-L1 expression, 40 patients were assessed and 70% of them were positive (≥1% in tumor cells). The confirmed response rate in patients with PD-L1 expression was 29% (95% CI, 13.2%-48.7%) per RECIST v1.1. The highest ORR of 35% (95% CI, 14.2%-61.7%) was observed in patients with a PD-L1 expression of 50% or more. A statistically significant difference in responses was observed between patients with PD-L1–positive tumors and those with PD-L1–negative tumors (Fisher’s exact two-sided test, P = .079). This trend of higher responses in patients with PD-L1–positive tumors was echoed with survival rates, where OS was correlated with PD-L1 status.
CD8 expression was also analyzed in 37 patients. Sixteen patients (43%) displayed ≥1% CD8-positive staining in their tumors. A higher ORR was observed in patients with ≥1% CD8 expression (95% CI, 7.3%-52.4%) versus patients with <1% CD8 expression (95% CI, 3.0%-36.3%) (Fisher’s exact two-sided test, P = .437). Fourteen patients had tumors that were positive for both PD-L1 and CD8 expression and the ORR for this subset was 29% (95% CI, 8.4%-58.1%).
BRAF mutations were found in 12 out of 38 evaluable patients (32%). It was discovered that the presence of a BRAF mutation led to lower ORRs. The ORR among those with a BRAF mutation was 8% (95% CI, 0.2%-38.5%) compared with 23% (95% CI, 9.0%-43.6%) among those without a BRAF mutation (Fisher’s exact two-sided test, P = .395). Of note, 9 of the patients who had a BRAF mutation also had a PD-L1 of 1% or higher.
The final analysis was for gene expression by RNA sequencing. From this assessment, Jaume Capdevila, MD, PhD, et al noticed a correlation between the best percentage change from baseline in the sum of diameters of target lesions and interferon-γ signature.
“Targeting PD-1/PD-L1 may provide a much-needed treatment option for patients with PDL1–positive advanced ATC, including the BRAF wild-type population,” study authors Capedevila et al concluded from the efficacy findings.
Any-grade adverse events (AEs) were reported in 98% of patients in the study. In 69% of patients, grade 3/4 AEs were reported. Only 45% of the AEs observed were attributed to treatment with spartalizumab. The most common any-grade AEs were diarrhea (11.9%), pruritus (11.9%), fatigue (7.1%), and pyrexia (7.1%). The grade 3/4 AEs observed were anemia (4.8%) and rash (2.4%). Immune-related AEs were seen in 10 patients and were believed to be treatment related. The most common immune-related AEs were grade 1/2 diarrhea (12%), pruritus (12%), rash (5%), and pruritus (2%), as well as rash macular, increased blood thyroid-stimulating hormone, and hypothyroidism, which each occurred in 2% of patients. The only serious AE was central nervous system brain metastasis, which was observed in 1 patient.
It was noted by Capedevila et al that these safety findings were consistent with those seen with other monoclonal antibodies that target PD-L1.
Spartalizumab was administered intravenously, once every 4 weeks at a dose of 400 mg to the patients in the international, multicenter, open-label study (NCT02404441). All patients continued to receive treatment until unacceptable toxicity, progressive disease as per irRC, or patient/physician decision. The primary end point for the phase II portion was to assess the antitumor activity of the drug through the ORR. The secondary end points were safety/tolerability, pharmacokinetics, ORR by irRC, PFS, OS, DOR, and disease control rate.
This first-in-human study was conducted based on prior clinical evidence supporting the use of drugs that target the interaction between the PD-1 receptor and its ligands, which leads to clinical activity in multiple tumor types, but mainly in tumors with PD-L1 expression. Considering that around 22% to 29% of ATC tumors express PD-L1, and spartalizumab blocks the interactions between PD-L1 and PD-L2, the investigators believed this study was likely to show promise.
Cadevila J, Wirth LJ, Ernst T, et al. PD-1 blockade in anaplastic thyroid carcinoma [Published Online May 4, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.02727