FDA analyses of survival in older adults with metastatic non–small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies

Abstract

Background

Among patients with newly diagnosed non–small cell lung cancer (NSCLC), approximately 70% occur in those above 65 years of age and more than half are metastatic or locally advanced NSCLC.

Methods

Retrospective analyses pooling data across 4 randomized clinical trials comparing programmed death 1 receptor (PD-1) or programmed death ligand 1 (PD-L1) to docetaxel for the treatment of patients with advanced or metastatic NSCLC with disease progression on or after a platinum-containing therapy were conducted. Demographics, efficacy, and safety data from these trials were pooled and aggregated based on age. The relative treatment effects on overall survival (OS) across age groups were evaluated using Kaplan–Meier methodology. A meta-analysis was performed comparing OS across age groups treated with PD-1/PD-L1 blocking antibodies compared with those treated with docetaxel, as a common control arm across trials. A Cox Proportional Hazards model, stratified by clinical trial, was used and a univariate and multivariate adjusted analysis of OS to further identify trends in efficacy across age groups.

Results

Among patients treated with PD-1/PD-L1 blocking antibodies enrolled across the 4 clinical trials, 42% were >65 years of age, 99% had ECOG performance status of 0–1, 75% had received 1 prior therapy, and 76% were diagnosed with Stage IV disease. In the pooled analysis of 2,824 patients across both arms, the treatment effects in age-defined subgroups were similar, with a hazard ratios (HR), unadjusted or adjusted, for OS of 0.71 (95% confidence interval 0.63, 0.80) in patients <65 years and 0.66 (0.57, 0.76) in patients ≥65 years of age. In patients ≥70 years, the HR for OS was 0.67 (0.55. 0.82) and in patients ≥ 75 years, the HR was 0.81 (0.58, 1.13). Estimated median OS in patients receiving PD-1/PD-L1 blocking antibodies versus docetaxel was 14.5 months versus 8.8 months in patients <65 years, 14.2 months versus 9 months in patients ≥65 years, 14.1 versus 9.2 months in patients ≥70 years, and 14.7 versus 9.5 months in the patients ≥75years.

Grade 3 or 4 treatment-related adverse events with PD-1/PD-L1 blocking antibodies were less frequent in patients ≥75 years (23%) compared to patients> 65 year ( 49%) and <65 years (47%), as were serious adverse events (30%, 32.5%, 15%); however, treatment-emergent adverse events leading to discontinuation of treatment (7%, 7%, and 5%) in those subgroups ≤65 years, >65 years, and >75 years, respectively, were similar.

Conclusions

Patients 65 and older with advanced and metastatic NSCLC, including those ≥75 years, seem to derive similar survival benefits from treatment with PD-1/PD-L1 blocking antibodies as patients <65 years of age. Patients 75 and older enrolled on these trials appear to tolerate PD-1/PD-L1 blocking antibodies and have a lower incidence of grade 3 or 4 treatment-emergent adverse events compared to the subgroup of patients <65 years of age.

Introduction

In the United States, lung cancer is the second most common cancer after prostate cancer in men and breast cancer in women [1]. Estimates for lung and bronchial cancer in the United States for 2018 are 234,030 new cases and 154,050 deaths, accounting for approximately 25% of cancer deaths [1]. Approximately 95% of all lung cancers are classified as either non–small cell lung cancer or small cell lung cancer, and the former comprises 80%–85% of the lung cancer cases in the US. The majority of these patients (approximately 57%) present with a locally advanced or metastatic stage, when curative treatments such as surgical resection and concurrent chemoradiation are not an appropriate option, leading to a 5-year survival of less than 5% for patients with Stage IV lung cancer [2].

Lung cancer is also a disease that predominantly affects older adults, with approximately 70% of new cases diagnosed in patients aged 65 years and older and 37% of new cases diagnosed in patients aged 75 years and older [3]. Although most cancers occur in older patients, accrual of older patients to cancer clinical trials has been a persistent challenge. In an FDA analysis of older adults with lung cancer enrolled on clinical trials leading to drug approval, approximately 40% of clinical trial participants were 65 years or older, compared with 70% of all new cases of stage IV lung cancer. This divergence appears to be driven by the dramatic difference seen for patients aged 75 years and older, comprising only 9% of clinical trial participants compared with 37% of new cases in the United States [4] (Fig. 1). As a result, the availability of data regarding the relative safety and efficacy of new drugs in older patients with lung cancer is limited.

The treatment landscape for advanced lung cancer has dramatically shifted in recent years with the introduction of programmed death 1 receptor (PD-1)/programmed death ligand 1 (PD-L1) blocking antibodies and targeted agents. Monoclonal antibodies targeting the PD-1, including the PD-L1, pathway have demonstrated significant activity in non–small cell lung cancer (NSCLC) with improvement in survival in the second-line setting. PD-1/PD-L1 blocking antibodies have been of particular interest when considering the concept of immunosenescence and its potential impact on treatment efficacy in older adults.

Nivolumab, a PD-1 blocking antibody, was approved in 2015 based on the survival results of the CheckMate 017 trial, a randomized, open-label study enrolling patients with metastatic squamous NSCLC who had experienced disease progression during or after 1 prior platinum-based chemotherapy regardless of PD-L1 status [5]. The application went through an expedited review process, given the survival advantage observed with nivolumab when compared with docetaxel (median overall survival [OS]: 9.2 v 6.0 months; hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.44–0.79; P < .001), the primary efficacy endpoint. The indication was later expanded to include the second-line treatment of patients with nonsquamous NSCLC. This approval was based on the CheckMate 057 trial, which demonstrated improved OS compared with docetaxel with a HR of 0.73 (95% CI 0.60–0.89; P = .0015), corresponding to an estimated median OS of 12.2 months among patients randomized to the nivolumab arm compared with 9.4 months in the docetaxel arm [6].

Pembrolizumab, also a PD-1 blocking antibody was initially granted accelerated approval in October 2015 based on a single arm analysis of an expansion cohort of KEYNOTE-01, limited to patients with metastatic NSCLC whose tumors express PD-L1 with disease progression on or after platinum-containing chemotherapy. In October 2016, pembrolizumab was approved for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA approved test, as follows: (a) first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (TPS ≥ 50%), with no epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations and (b) treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥ 1%) with disease progression on or after platinum-containing therapy. These supplemental approvals were based on 2 randomized, active-controlled trials demonstrating statistically significant improvements in progression-free survival (PFS) and OS for patients randomized to pembrolizumab compared with chemotherapy. In KEYNOTE-024, patients with previously untreated metastatic NSCLC and TPS ≥ 50% who received pembrolizumab had a statistically significant improvement in OS (HR 0.60; 95% CI 0.41–0.89; P = .005) and significant improvement in PFS (HR 0.50; 95% CI: 0.37–0.68, P < .001) compared to patients who received platinum-doublet chemotherapy. In KEYNOTE-010, patients with disease progression on or after platinum-containing therapy and TPS ≥ 1% were randomized to receive pembrolizumab 2 mg/kg IV every 3 weeks (Q3W), pembrolizumab 10 mg/kg IV Q3W, or docetaxel Q3W. The HR for OS was 0.71 (95% CI: 0.58–0.88) with P < .001 comparing the pembrolizumab 2 mg/kg arm with the docetaxel arm, while the HR for OS was 0.61 (95% CI: 0.49–0.75) with P < .001 for the comparison of the pembrolizumab 10 mg/kg arm with the docetaxel arm [7].

More recently in 2017, FDA granted accelerated approval to pembrolizumab in combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic NSCLC. Approval was based on overall response rate and PFS [8].

In 2016, FDA approved atezolizumab, a PD-L1 blocking antibody, for the treatment of patients with metastatic NSCLC whose disease had progressed during or following platinum-containing chemotherapy. The approval was based on the results of 2 randomized open-label trials (OAK and POPLAR) that demonstrated consistent results in efficacy and safety in patients with NSCLC. The OAK trial demonstrated improved OS (HR 0.74, 95% CI: 0.63–0.87, P = .0004), corresponding to an estimated median OS of 13.8 months in the atezolizumab arm and 9.6 months in the chemotherapy arm. The POPLAR trial also suggested an improvement in OS (HR 0.69, 95% CI: 0.52–0.92) corresponding to estimated median OS of 12.5 months and 9.7 months for the atezolizumab and docetaxel arms, respectively [9].