Pembrolizumab Plus Amrubicin in Patients With Relapsed SCLC: Multi-Institutional, Single-Arm Phase 2 Study

Abstract

Introduction In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor. Preclinical study suggested that anthracycline agent might induce immunogenic cell death and work synergistically with immune checkpoint inhibitors. Methods Patients with relapsed SCLC who relapsed after completion of platinum-containing regimen were registered. Patients were treated with pembrolizumab (200 mg, flat dose on d 1, every 3 wk for 2 y) plus AMR (40 mg/m 2 on d 1–3, every 3 wk until progression). Primary end point was overall response rate (ORR). Secondary end points consisted of progression-free survival (PFS), overall survival, and safety. On the basis of the hypothesis that this treatment will improve ORR from 20% to 40% (0.1 of one-sided α and power of 0.8), 25 patients are required (trial identifier: NCT03253068). Results Between November 2017 and October 2019, a total of 25 patients were enrolled. Most participants (88%) relapsed within 90 days after platinum-containing therapy and all patients were immune checkpoint inhibitor-naive. ORR, the primary end point, was 52.0% (95% confidence interval [CI]: 31.3%–72.2%). Median PFS was 4.0 months (95% CI: 2.8–7.0 mo), and PFS rate at 1 year was 14.4%. Median overall survival was 10.6 months (95% CI: 7.3–21.3 mo). Common adverse events greater than or equal to grade 3 were neutropenia (64%), leukopenia (40%), and febrile neutropenia (16%). No treatment-related deaths occurred. Conclusions Among patients with relapsed SCLC, pembrolizumab plus AMR was effective and tolerable.

Efficacy and safety of amrubicin monotherapy after atezolizumab plus carboplatin and etoposide in patients with relapsed small-cell lung cancer

“…Results of a single-arm phase II trial of pembrolizumab, an ICI, in combination with amrubicin in patients with relapsed SCLC were recently reported [ 39 ]. Patients had not received any prior ICIs, but the response rate was 52.0%, the median PFS was 4.0 months, and the median OS was 10.6 months.…”

Efficacy and Safety of Amrubicin in Small Cell Carcinoma Previously Treated with Immune Checkpoint Inhibitors and Chemotherapy

“…Short progression-free survival of 1.4 to 1.9 months has been reported [ 12 , 13 , 14 ]. By contrast, a progression-free survival of 4.0 months was reported in a phase II trial where pembrolizumab was used in addition to amrubicin as a second-line treatment for ES-SCLC [ 15 ]. Anthracyclines such as amrubicin promote the mobilization and recruitment of T-cell antigen-presenting cells to the tumor sites, apart from stimulating immunogenic cell death and interferon secretion [ 16 , 17 , 18 ].…”

Phase I study of amrubicin plus cisplatin and concurrent accelerated hyperfractionated thoracic radiotherapy for limited‐disease small cell lung cancer: protocol of ACIST study

“…Immunotherapy using immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD‐1), programmed death‐ligand 1 (PD‐L1), and cytotoxic T‐lymphocyte‐associated protein 4, either as single agents or combined with cytotoxic chemotherapy, has revolutionized the treatment of several solid tumors, including SCLC. 18 A recent study has shown that the addition of an anti‐PD‐1 antibody, pembrolizumab, to AMR for relapsed SCLC could afford a remarkable ORR of 52% and PFS rate of 14.4% at one year, 19 indicating the promising effect of AMR when combined with ICIs. For some patients with LD‐SCLC who would benefit from ICIs, a combination with AP may be an optimal strategy in the future.…”