Phase II Data Suggest Predictive Value of Preexisting CD8+ T Cells in SCLC

Anish Thomas, MD

Anish Thomas, MD

Findings from a phase II study in patients with small cell lung cancer (SCLC) suggested tumor immune phenotypes can be predictive of response to immune checkpoint blockade. Responses to the combination of durvalumab (Imfinzi) plus olaparib (Lynparza) were observed in all patients where tumors had an inflamed phenotype.

“Tumor CD8-positive T-cell infiltration has been linked to antitumor activity in patients with advanced melanoma and NSCLC treated with immune checkpoint inhibitors,” study authors, led by Anish Thomas, MD, of the National Cancer Institute, wrote in their recently published report. “Our observation extends these findings to relapsed SCLC and suggests that a preexisting CD8-positive T-cell response may be predictive of benefit from immune checkpoint inhibitor—based therapies in SCLC.”

In the open-label, single-arm phase II trial, patients with SCLC were treated with the combination of durvalumab plus olaparib. To be eligible, patients had to have histologically confirmed SCLC with at least 1 prior platinum-based chemotherapy regimen received. Patients also had to have an ECOG performance status of 2 or lower with adequate organ and bone marrow function. Patients that previously received treatment with an immune checkpoint inhibitor were not excluded from the study, although those who had received prior treatment with a PARP inhibitor were excluded. Additionally, those with symptomatic brain metastases, autoimmune disease, pneumonitis, interstitial lung disease, or inflammatory bowel disease were also excluded from the trial.

Patients received 1500 mg of durvalumab intravenously every 28 days plus 300 mg olaparib tablets twice daily on a continuous basis.

The median age of the patients was 64 years (range, 42-76) and 55% were female. Half of the patients had received only 1 prior line of therapy but 15% had received 3 prior lines. Sixty percent of patients were resistant or refractory to platinum after first-line chemotherapy and 40% were platinum sensitive.

Of the 19 evaluable patients, 18 underwent tissue biopsies before treatment while 10 tissue biopsies were performed during treatment; they were assessed for PD-L1 expression and T-cell infiltration by immunohistochemistry. Tumors were categorized within 3 groups, including “desert,” defined as tumors with low prevalence of CD8-positive T cells; “excluded” for tumors expressing CD8-positive T cells exclusively in the stroma adjacent or within the tumor; and “inflamed,” including tumors that expressed CD8-positive T cells in direct contact with tumor cells.

“To our knowledge, this study is the first to assess immune phenotypes in serial SCLC biopsy specimens obtained during treatment,” the study authors explained. “Biopsy specimens were obtained from the same lesion to minimize biological variability.”

Overall, 21% of tumors presented with an inflamed phenotype, while 14% were categorized as a desert phenotype and 54% had excluded phenotypes. PD-L1 expression was identified in 8 patients (44%), although the expression levels were usually below 20% of cells. Inflamed phenotypes were associated with PD-L1 expression, and responses were observed in all cases where pretreatment tumors had an inflamed phenotype.

There was 1 confirmed complete response and 1 partial response (PR). Additionally, 4 patients had stable disease, including 2 with prolonged stable disease of 8 months or greater. Overall, 13 patients had progressive disease, including 1 patient that discontinued treatment after 1 cycle due to brain-only disease progression but had a PR in systemic disease sites for 6 months and a second patient that had a PR at first restaging but progressive disease on a confirmatory scan.

The investigator-assessed objective response rate (ORR) was 10.5% (95% CI, 1.3%-33.1%). Median progression-free survival was 1.8 months (95% CI, 0.9-2.4 months), and the median overall survival (OS) was 4.1 months (95% CI, 2.4-9.2 months). A clinical benefit was observed in 4 (21.1%) of the patients (95% CI, 6.1%-45.6%). The primary endpoint of ORR was not met however.

The most common adverse events (AEs) reported in this study included anemia (80%), lymphopenia (60%), leukopenia (50%), fatigue (45%), and thrombocytopenia (45%). Nine patients experienced grade 3/4 treatment-related AEs, including anemia, lymphopenia, thrombocytopenia, and hypophosphatemia. Additionally, 25% of patients experienced an increase in thyroid-stimulating hormone levels, which were asymptomatic. There were no other neurological or immune-related AEs reported. Only 1 patient required a dose reduction of olaparib due to grade 3 anemia. No patients discontinued treatment due to AEs.

According to analysis of the biopsies, responding tumors showed dense T-cell infiltration; this indicates that responses may be amplified with the presence of preexisting immunity during treatment. Furthermore, tumors that did not respond to therapy had minimal or no tumor-infiltrating immune cells, suggesting the absence of preexisting tumor-specific T cells. Some nonresponding tumors also demonstrated a pattern in which the immune cells were restricted to the stroma, suggesting the presence of immunosuppressive mechanisms.

“Defining biomarkers predictive of response in SCLC is challenging because in this disease, biopsies are generally not performed at relapse and biopsy specimens usually provide limited tissue for analyses,” Thomas et al concluded. “Further, the relevance of the tumor immune phenotype to the response of SCLC was previously unknown. Consistent with the published literature, we observed that PD-L1 expression was in most cases limited to a minority of tumor cells and or tumor-infiltrating immune cells."

This trial was limited by its small sample size and the single-arm design; there were also no comparator groups, limiting the ability to assess both clinical and biomarker response to the combination. Analysis of a larger cohort is necessary to confirm these findings and identify patients with SCLC that may be likely to benefit from immune checkpoint inhibitor therapy.

Reference:

Thomas A, Vilimas R, Trindade C, et al. Durvalumab in Combination with Olaparib in Patients with Relapsed SCLC: Results from a Phase II Study. J Thorac Oncol. 2019;14(8):1447-1457. https://doi.org/10.1016/j.jtho.2019.04.026