Immunotherapy

Pembrolizumab

Pembrolizumab is an immunoglobulin G (IgG)4 monoclonal antagonist antibody to PD-1 that is approved for firstline treatment of patients with advanced EGFR/anaplastic lymphoma kinase (ALK) wild-type NSCLC whose tumors have ≥50% PD-L1 expression based on the 22C3 pharmDx test. Pembrolizumab was first approved in 2015 for use as second-line treatment for patients with lung cancer. This was based on the KEYNOTE 001 and KEYNOTE 010 trials. KEYNOTE 001 was a Phase I trial assessing efficacy of pembrolizumab in paitents with advanced NSCLC. Objective response rate (ORR) was 19.4% (95%CI: 16–23) with median overall survival (OS) of 12 months (95%CI: 9.3–14.7). Interestingly, patients with at least 50% PD-L1 tumor expression had ORR of 45.2% (95%CI: 33.5–57.3) and median OS was not reached.7 The KEYNOTE 010 trial was a Phase II/III trial that compared pembrolizumab to docetaxel in patients with advanced NSCLC who previously received treatment. Compared to docetaxel, improved median OS was observed with pembrolizumab at 2 mg/kg and 10 mg/kg—10.4 months and 12.7 months vs 8.5 months for docetaxel treated group (HR: 0.71; 95%CI: 0.58–0.88 and 0.61; 95%CI: 0.49–0.75, respectively). However, progression-free survival (PFS) was no different in any of the treatment arms. It should be noted that in patients with at least 50% tumor PD-L1 expression (442 patients) response rates were ~30% with pembrolizumab treatment vs 8% in docetaxel-treated patients (P<0.0001 and P<0.0001, respectively). These patients also had improved OS and PFS—pembrolizumab 2 mg/kg and 10 mg/kg, median OS was 14.9 months and 17.3 months vs 8.2 months for docetaxel-treated group (HR: 0.54; 95%CI: 0.38–0.77 and 0.50, 95%CI: 0.36–0.70, respectively).8


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Given the benefit of pembrolizumab in advanced NSCLC with tumors expressing at least 50% PD-L1, trials were designed to determine the benefit of pembrolizumab as first-line therapy. The KEYNOTE-024 trial, was a Phase III study comparing pembrolizumab monotherapy (200 mg intravenous (IV) every 3 weeks) to standard platinum-doublet chemotherapy in 305 patients with advanced, untreated, EGFR/ALK wild-type NSCLC with PD-L1 tumor expression of at least 50%.9 Of the 1,653 screened patients with tumor tissue available, 30% were found to have tumors with at least 50% PD-L1 expression, of which only 305 patients were enrolled. At median follow-up (11.2 months) the primary outcome, PFS, was increased compared to platinum-doublet chemotherapy (10.3 vs 6 months; HR: 0.50; 95%CI: 0.37–0.68). OS was also prolonged with pembrolizumab compared to platinum-doublet chemotherapy (HR: 0.60; 95%CI: 0.41–0.89). ORR (based on RECIST) was 45% with pembrolizumab compared to 28% with chemotherapy with median duration of response 12.1 vs 5.7 months. Updated results showed that the median survival with pembrolizumab was 30 months vs 14.2 months (HR: 0.63; 95%CI: 0.47–0.86; 12 month OS rate 70% vs 55% (43.7% of patients in chemotherapy group crossed over to receive pembrolizumab after disease progression).10

To understand if benefits with front-line pembrolizumab extended to advanced stage NSCLC patients with tumor PD-L1 tumor expression of at least 1%, the KEYNOTE-042 study was initiated. This Phase III trial, comparing single agent pembrolizumab with standard, histology-appropriate, platinum-doublet chemotherapy enrolled 1,274 patients.11 Patients were stratified by tumor levels (>50% vs 1–49%) and OS was the primary endpoint. At median follow-up of 12.8 months, median OS with pembrolizumab was 16.7 months and with chemotherapy was 12.1 months (HR: 0.81, P=0.0018). In patients with at least 50% PD-L1 expression (599 patients) was 20 months vs 12 months in patients treated with chemotherapy (HR: 0.69; 95%CI: 0.56–0.85). In exploratory analysis, OS of patients with PD-L1 expression between 1 and 49% was 13.4 months vs 12.1 months (HR: 0.92; 95%CI: 0.77–1.11). This suggests that the survival benefit with pembrolizumab in patients with advanced stage NSCLC is most profound for those patients with tumor PD-L1 expression of at least 50%. Taken together, these studies show a significant survival benefit with the use of pembrolizumab in patients with advanced NSCLC whose tumors express at least 50% PD-L1. However, in patients with tumor PD-L1 expression ≤50% there does not appear to be a survival advantage with pembrolizumab. Understanding, how to improve response and outcomes to immunotherapy in those patients with advanced NSCLC with less than 50% PD-L1 expression is extremely important.

Nivolumab

Nivolumab is another IgG4 monoclonal antibody antagonist to PD-1. Similar to pembrolizumab, nivolumab was evaluated in recurrent NSCLC patients in two separate trials. CheckMate 017 and CheckMate 057 compared nivolumab to docetaxel in patients with recurrent squamous cell lung cancer and nonsquamous NSCLC, respectively. Nivolumab was also evaluated as first-line therapy. CheckMate 026 was a Phase III randomized trial of 541 patients with advanced NSCLC who were PD-L1 positive (at least 1% of tumor cells expressing PD-L1) and had not received previous treatment. Patients were randomized to nivolumab (3 mg/kg IV every 2 weeks) or standard first-line, histology-based, platinum doublet chemotherapy. The co-primary endpoints, PFS and OS were not improved with nivolumab (HR for disease progression and death in patients with >5% PD-L1 tumor expression: 1.15; 95%CI: 0.91–1.45; HR for death: 1.02; 95%CI: 0.80–1.30), this included patients with PD-L1 expression of >50% (HR: 1.07; 95%CI: 0.77–1.49).12 Further exploratory analysis was performed to determine the effect of tumor mutational burden (TMB) on outcomes. Among patients with high TMB who received nivolumab, the response rate was 47% compared to 28% in patients treated with chemotherapy. PFS was also increased, 9.7 months vs 5.8 months (HR: 0.62; 95%CI: 0.38–1).12 OS was similar between the groups. The exact reasons for lack of survival benefit with nivolumab in CheckMate 026, even in patients with high tumor PD-L1 expression are unclear. Currently nivolumab is not approved for use as front-line therapy for the management of advanced NSCLC patients.

Atezolizumab

Atezolizumab is an IgG1 antagonist antibody to PD-L1 engineered to avoid antibody-dependent, cell-mediated cytotoxicity of activated T cells that may express PD-L1. Atezolizumab is FDA approved for treatment of patients with metastatic NSCLC whose disease has progressed following platinum-containing chemotherapy. In the Phase III OAK trial, 1,225 patients with advanced NSCLC, PD-L1 unselected, treated with one or more platinum-based combination therapies were randomized to either single agent atezolizumab (1,200 mg IV every 3 weeks) or docetaxel. The results of this study were comparable to those observed with pembrolizumab and nivolumab.13,14

First-line atezolizumab monotherapy was recently studied in patients with locally advanced or metastatic NSCLC, PD-L1-unselected (B-F1RST trial). In this trial, 152 patients received atezolizumab 1,200 mg every 3 weeks until disease progression or loss of clinical benefit. The authors were interested in assessing whether blood-based TMB can be used as a biomarker to predict benefit from atezolizumab. High TMB was defined as ≥16 (mutations per megabase) while low TMB was defined as as <16 (mutations per megabase). ORR in patients with high TMB vs low TMB was 28.6% compared to 4.4%. PFS in TMB high vs TMB low patients was 4.6 months compared to 3.7 months (HR: 0.66; 90%CI: 0.42–1.02).15 Based on these interim results there is an ongoing randomized Phase III study, the B-FAST trial (NCT03178552) comparing atezolizumab to platinum-based chemotherapy in patients with high TMB based on a blood based assay. In addition, the BIRCH trial was a Phase II trial designed to examine the use of atezolizumab 1,200 mg every 3 weeks as monotherapy in patients with advanced NSCLC who had received zero to up to two lines of treatment and had PD-L1 expression ≥5% based on the SP142 immunohistochemistry assay. The study found that patients achieved ORR around 20% and OS was 23.5 months (95%CI: 18.1 months to not estimable (NE)) with front-line treatment, 15.5 (95%CI: 12.3–19.3 months) and 13.2 (95%CI: 10.3–17.5 months) months in patients treated with second-line or third-line treatment, respectively.16

Durvalumab

Durvalumab, a human monoclonal PD-L1 antibody, is also being studied in patients with advanced NSCLC. Previously, durvalumab was FDA approved for use in patients with unresectable, stage III NSCLC who have not progressed following concurrent radiation and platinum-based chemotherapy based on the PACIFIC trial.17 In the advanced stage setting, the MYSTIC trial is a Phase III study that enrolled 1,118 patients with metastatic NSCLC and randomly assigned them to durvalumab alone, durvalumab plus tremelimumab (at CTLA-4 inhibitor) or chemotherapy. Primary endpoints were OS for durvalumab vs chemotherapy and OS and PFS for durvalumab plus tremelimumab vs chemotherapy in patients with 25% or greater PD-L1 expression on tumor cells. Results demonstrated that of the 488 patients with ≥25% PD-L1 tumor cell expression, durvalumab alone (16.3 months vs 13.9 months; HR: 0.75; 97.5%CI: 0.564–1.019; P=0.036) or in combination with tremelimumab (11.9 vs 12.9 months; HR: 1.05; 99.5%CI: 0.722–1.534; P=0.705) did not improve OS or PFS as compared to chemotherapy.18

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