Randomized phase 2 trial of pembrolizumab alone or in combination with low dose chemotherapy for patients with Non-Small cell lung cancer and poor performance status
Mené sur 43 patients atteints d'un cancer du poumon non à petites cellules de stade avancé et présentant un faible indice de performance, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse, du pembrolizumab seul ou en combinaison avec de faibles doses de chimiothérapie (carboplatine, paclitaxel)
Purpose: Immunotherapy alone or in combination with chemotherapy has become the standard of care for medically fit patients who have advanced non-small cell lung cancer (NSCLC) without a driver mutation. The optimal treatment for patients with poor performance status remains an active area of investigation.
Patients and Methods: Patients with advanced NSCLC and an Eastern Cooperative Oncology Group performance status (PS) of 2 were randomized to single-agent pembrolizumab at 200 mg every 3 weeks (Arm A) or the same dose of pembrolizumab combined with weekly carboplatin area under the curve 1 and paclitaxel 25 mg/m2 (Arm B). The co-primary outcomes were differences in response rates between the Arms and comparison of each Arm to a historical control. Progression free survival (PFS) and overall survival (OS) were secondary outcomes using intent to treat analyses. Optional blood samples were obtained at baseline and after 2 cycles of treatment, and immune cells were measured using flow cytometry. A subset of post-treatment blood samples were analyzed using single-cell sequencing.
Results: 43 patients enrolled with 20 patients evaluable for response in each arm. All enrolled patients were included in survival analyses. Therapy was generally well tolerated with no treatment-related deaths in either arm. Both Arms exceeded the predefined historical control response rate of 10 % (Arm A = 35 %, P = 0.0002; Arm B = 45 %, P < 0.0001). Response rates favored Arm B but the difference was not statistically significant (P = 0.75). Median PFS and OS were not significantly different between the two arms. To compare survival outcomes of either pembrolizumab-based therapy to historical control of platinum-based chemotherapy for patients with PS 2, the two arms were combined. Median PFS was similar to historical control of platinum-based chemotherapy (4.6 months vs 4.6 months historical control). However, overall survival favored pembrolizumab-based therapy at 12 months (44 % vs 31 % historical control, P = 0.062) and 24 months (33 % vs 11 % historical control, P = 0.0001). Twenty patients provided optional blood samples for biomarker analyses. Consistent with prior reports, a numerically longer (but not significant) OS was observed in patients with low regulatory T cells (CD4 + FoxP3 + ) at baseline (14.5 vs 4.6 months, P = 0.068). Abundance of myeloid derived suppressor cells (CD14 + HLA DR-) at baseline did not correlate with clinical outcomes. Single-cell sequencing identified several significant differences in gene expression profiles within the CD14 + cell population for responding and non-responding patients treated with chemoimmunotherapy.
Conclusions: For patients with poor performance status, adding very low dose chemotherapy to pembrolizumab did not significantly improve clinical outcomes compared to pembrolizumab alone. Patients receiving either of these pembrolizumab-based regimens demonstrated better long-term survival when compared to historical outcomes of platinum-based chemotherapy for the PS 2 population.