The Role of Immunotherapy in Extensive Stage Small-Cell Lung Cancer: A Review of the Literature

Abstract

Lung cancer is the second most common cancer in both sexes worldwide. Small-cell lung cancer (SCLC) is a form of neuroendocrine tumor, which is classified into limited and extensive-stage disease and shows excellent initial response to chemotherapy; however, almost all patients relapse later. During the past few years, several clinical trials have evaluated the effect of addition of immunotherapy to conventional chemotherapy in patients with extensive SCLC. Checkpoint inhibitors are currently under investigation, especially the CTLA-4 and PD-1/PD-L1 inhibitors. Nowadays, evidence show a statistically significant survival benefit of adding atezolizumab, an IgG1 monoclonal antibody targeting against PD-L1, to platinum-based chemotherapy plus etoposide in patients who have not received any previous systemic therapy. Furthermore, the role of nivolumab, an IgG4 anti-PD-1 monoclonal antibody, is significant for the treatment of relapsed SCLC cases. Recently, pembrolizumab was the first immunotherapeutic agent to be approved by the FDA for patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least one other prior line of chemotherapy. Nevertheless, prognostic biomarkers to immunotherapy response remain to be discovered.

Molecular Signature of Small Cell Lung Cancer after Treatment Failure: The MCM Complex as Therapeutic Target

“…Due to the rapid progression and quite invasive nature, approximately 70% of SCLC patients are advanced stage at the time of initial diagnosis [ 3 ]. Platinum-based chemotherapy is the first-line treatment for patients with ED-SCLC [ 4 , 7 ]. SCLC cells respond to this treatment initially, but over the course of treatment, they acquire resistance to treatment, and most patients relapse.…”

“…Platinum-based chemotherapy is used as the initial treatment for patients with ED-SCLC, and it has improved survival [ 4 ]. A clinical feature of SCLC is that it responds efficiently to treatment initially but then acquire drug resistance during treatment [ 5 , 6 ].…”

Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy

“…With regard to SCLC, nivolumab was also tested for pretreated patients with SCLC in the CheckMate-032 trial, obtaining approval from the FDA. This trial showed an objective response rate (ORR) of 10% with nivolumab and 23% with nivolumab + ipilimumab, with grade 3–4 adverse effects of 14% and 33%, respectively [ 74 ]. Soon after, the addition of atezolizumab (anti-PD-L1) to CT in the first-line SCLC treatment in the IMpower133 trial achieved the first OS improvement in decades [ 70 ].…”

“…A similar reduction in the death risk was also identified in the phase II CASPIAN trial, which included the PD-L1 inhibitor durvalumab in combination with CT [ 71 ]. Thanks to the results of the KEYNOTE-028 and KEYNOTE-158 trials, the FDA approved in 2019 the use of pembrolizumab as monotherapy for patients with metastatic SCLC with disease progression on or after platinum-based CT and at least one other prior line of therapy [ 74 ].…”

“…Besides, there are several trials currently ongoing evaluating different uses of ICIs is SCLC. Among them, the phase III CheckMate-331 trial (nivolumab vs topotecan/amrubicin), the phase III CheckMate-451 trial (nivolumab vs nivolumab + ipilimumab vs placebo), the phase III KEYNOTE-604 trial (pembrolizumab + platinum/etoposide vs platinum/etoposide), the phase III CASPIAN trial (durvalumab ± tremelimumab + CT vs CT) and the phase III MERU trial (Rova-T + dexamethasone vs placebo (after CT)) [ 74 ].…”