Presence of few PD‐1‐expressing tumor‐infiltrating immune cells is a potential predictor of improved response to salvage chemotherapy following nivolumab for non‐small cell lung cancer: An exploratory case series

Abstract

BackgroundThe combination of PD‐1 inhibitors and cytotoxic drugs is reported to enhance anti‐tumor activity in non‐small cell lung cancer; however, the underlying synergistic mechanisms remain uncertain. This retrospective case series was designed to investigate objective response and survival rates of salvage chemotherapy following nivolumab and explore the immunohistochemical profiles of tumor‐infiltrating immune cells.MethodsThe medical records of 37 patients administered nivolumab were retrospectively reviewed. Overall response rate and progression‐free survival were compared among three groups: salvage chemotherapy following nivolumab, nivolumab therapy alone, and chemotherapy preceding nivolumab.ResultsEight cases met the study criteria. Salvage chemotherapy following nivolumab improved the overall response rate to 62.5% (95% confidence interval [CI] 34.4–90.6%; P = 0.004) and median progression‐free survival to six months (95% CI 4.6–7.4; P = 0.016), compared to nivolumab alone and preceding chemotherapy. The response to salvage chemotherapy was not associated with tumor PD‐L1 expression. A partial response was achieved in four cases with ≤ 5% and ≤ 2.9 cells/mm2 of PD‐1+ immune cells, whereas stable disease and progressive disease were observed in three cases with ≥ 30% and ≥ 12.7 cells/mm2. Responders had fewer PD‐1+ immune cells than non‐responders (percentage P = 0.028; density P = 0.034).ConclusionSalvage chemotherapy following nivolumab improved anti‐tumor activity regardless of tumor PD‐L1 status, but nivolumab following chemotherapy did not. The presence of few PD‐1+ tumor‐infiltrating immune cells may serve as a potential predictor of response to salvage chemotherapy. Further studies involving a large cohort are needed to clarify how nivolumab re‐sensitizes the tumor immune microenvironment to chemotherapy.

Dynamics of blood neutrophil‐related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non‐small cell lung cancer: A hypothesis‐generating study

“…In addition, disease progression during first‐line chemotherapy for NSCLC was reported to correlate with high levels of circulating MDSCs . Combining these findings with the results of our previous studies, we hypothesize that both the exhaustion levels of cytotoxic T cells and interference with myeloid cells may affect the efficacy of nivolumab and subsequent salvage chemotherapy (Fig ).…”

“…In contrast, our previous studies showed that the presence of a few PD‐1 + TILs was associated with the response to salvage chemotherapy, as well as nivolumab treatment . However, we did not clarify why preceding nivolumab therapy showed less antitumor activity in the responders to salvage chemotherapy.…”

“…This single‐institute, exploratory study was performed retrospectively, following our previously published study . In brief, patients with recurrent or advanced NSCLC underwent salvage chemotherapy following nivolumab treatment between April 2016 and December 2017.…”

“…We recently reported that salvage chemotherapy following nivolumab increased the response in some patients with NSCLC, regardless of tumor PD‐L1 status . In addition, the presence of minimal PD‐1 expression on tumor‐infiltrating lymphocytes (TILs) before treatment may be associated with improved response to salvage chemotherapy . However, we did not clarify the mechanisms that created these synergistic effects during nivolumab treatment.…”

“…The combination of immunotherapy and chemotherapy, including salvage chemotherapy following PD‐1 inhibitor therapy, is a promising treatment for patients with non‐small cell lung cancer (NSCLC) . We recently reported that salvage chemotherapy following nivolumab increased the response in some patients with NSCLC, regardless of tumor PD‐L1 status . In addition, the presence of minimal PD‐1 expression on tumor‐infiltrating lymphocytes (TILs) before treatment may be associated with improved response to salvage chemotherapy .…”