A phase 2 trial of chemotherapy plus pembrolizumab in patients with advanced non–small cell lung cancer previously treated with a PD‐1 or PD‐L1 inhibitor: Big Ten Cancer Research Consortium BTCRC‐LUN15‐029

Abstract

Background Immunotherapy using a checkpoint inhibitor (CPI) alone or in combination with chemotherapy is the standard of care for treatment‐naive patients with advanced non–small cell lung cancer (NSCLC) without driver mutations for which targeted therapies have been approved. It is unknown whether continuing CPI treatment beyond disease progression results in improved outcomes. Methods Patients who experienced progressive disease (PD) after a clinical benefit from chemotherapy plus a CPI were enrolled. Patients received pembrolizumab (200 mg every 3 weeks) plus next‐line chemotherapy. The primary end point was progression‐free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Key secondary end points included the overall survival (OS), clinical benefit rate, and toxicity. The authors’ hypothesis was that continuing pembrolizumab beyond progression would improve the median PFS to 6 months in comparison with a historical control of 3 months with single‐agent chemotherapy alone. Results Between May 2017 and February 2020, 35 patients were enrolled. The patient and disease characteristics were as follows: 51.4% were male; 82.9% were current or former smokers; and 74.3%, 20%, and 5.7% had adenocarcinoma, squamous cell carcinoma, and NSCLC not otherwise specified, respectively. The null hypothesis that the median PFS would be 3 months was rejected (p < .05). The median PFS was 5.1 months (95% confidence interval [CI], 3.6–8.0 months). The median OS was 24.5 months (95% CI, 15.6–30.9 months). The most common treatment‐related adverse events were fatigue (60%), anemia (54.3%), and nausea (42.9%). There were no treatment‐related deaths. Conclusions Pembrolizumab plus next‐line chemotherapy in patients with advanced NSCLC who experienced PD after a clinical benefit from a CPI was associated with statistically significant higher PFS in comparison with historical controls of single‐agent chemotherapy alone.

Immunotherapy partners after progression: Right place, right time?

“…Lung‐MAP S1800A also offers a contemporary control where the second‐line chemotherapy arm did receive immunotherapy in the frontline setting. The increased mOS of 24.5 months in Salous et al.’s trial 5 is even more impressive in comparison with the 11.6‐month mOS in this contemporary control.…”

“…In a phase 2 study, Salous et al 5 . hypothesize that continuing immunotherapy with a new chemotherapy partner at the time of disease progression could improve outcomes over chemotherapy alone.…”

“…Both the Salous et al. study 5 and the Lung‐MAP S1800A study excluded patients on ICIs for less than 12 weeks in an attempt to exclude patients with primary resistance to immunotherapy. Primary resistance can occur because of poor tumor antigen presentation, insufficient tumor neoantigens, a lack of immune cell infiltration into the tumor microenvironment, and inhibition from myeloid‐derived suppressor cells or T regulatory cells.…”

Study protocol of KeyPemls‐004: A phase 2 study of pembrolizumab in combination with plinabulin and docetaxel in previously treated patients with metastatic non‐small cell lung cancer and progressive disease (PD) after immunotherapy (PD‐1/PD‐L1 inhibitor) alone or in combination with platinum‐doublet chemotherapy

“…In a single-arm phase II study, patients who progressed after clinical benefit from ICI therapy were given pembrolizumab combined with chemotherapy, and the median PFS was 5.1 months, which was better than the historical control of chemotherapy alone of 3 months. 19 Meanwhile, a double-blind randomized phase II trial studied continuation of pembrolizumab with additional chemotherapy after progression with anti-PD-1/PD-L1 therapy in patients with advanced NSCLC, and reported no statistical difference in PFS and OS between the pembrolizumab-chemotherapy and placebo-chemotherapy cohorts. However, in subgroup analysis, patients with PD-L1 ≥ 50% of tumor cells showed a favorable clinical outcome in the pembrolizumab-chemotherapy arm.…”

“…The major explorations for overcoming immunotherapy resistance are focused on combination strategies, such as combination with targeted therapy or chemotherapy, or dual immunotherapy. In a single‐arm phase II study, patients who progressed after clinical benefit from ICI therapy were given pembrolizumab combined with chemotherapy, and the median PFS was 5.1 months, which was better than the historical control of chemotherapy alone of 3 months 19 . Meanwhile, a double‐blind randomized phase II trial studied continuation of pembrolizumab with additional chemotherapy after progression with anti‐PD‐1/PD‐L1 therapy in patients with advanced NSCLC, and reported no statistical difference in PFS and OS between the pembrolizumab‐chemotherapy and placebo‐chemotherapy cohorts.…”