Vinay Gupta, MD
Several clinical trials have evaluated the addition of immunotherapy to standard chemotherapy in the frontline treatment of patients with advanced non–small cell lung cancer (NSCLC), explained Vinay Gupta, MD, all of which echo similar conclusions: these combinations are a mainstay in this population.
In a presentation during the 2018 OncLive®
State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, Gupta, an oncologist/hematologist at Saint Luke’s Cancer Specialists, highlighted 3 specific trials that have demonstrated this benefit in both advanced- and earlier-stage settings.
Immunotherapy has shown a consistent benefit in patients with advanced or metastatic disease, whether it’s used in combination with chemotherapy or with angiogenesis inhibition. However, its benefit is not restricted to this setting, explained Gupta, as was demonstrated by the phase III PACIFIC trial after chemoradiation.
“Prior to these data, the standard of care was concurrent platinum-based chemoradiation, which resulted in modest outcomes and a poor median survival,” said Gupta. “Approximately 80% to 85% of patients would progress to stage IV disease.”
In the trial, adult patients with locally advanced, unresectable, stage III NSCLC were randomized 2:1 to receive either 10 mg/kg of durvalumab (Imfinzi) every 2 weeks for up to 1 year (n = 476) or placebo (n = 237). Patients with either nonsquamous and squamous histologies were eligible to participate if, after receiving ≥2 cycles of platinum-based chemotherapy and radiation, they had not progressed on therapy (n = 713). Therapy was given within 42 days of completing concurrent chemoradiation and continued until disease progression or unacceptable toxicity.
Patients were stratified by age (<65 and ≥65), sex, and smoking history. PD-L1 status was not required. Although patients with EGFR mutations were eligible to enroll, they accounted for just a small percentage of the study population (n = 43).
Coprimary endpoints were progression-free survival (PFS) and overall survival (OS). The median PFS rates, as reported in the interim analysis published in the New England Journal of Medicine
, were 16.8 months and 5.6 months with durvalumab consolidation and placebo, respectively (HR, 0.52; 95% CI, 0.42-0.65; P
<.001). The 18-month PFS rates were 44.2% with durvalumab consolidation and 27% with placebo. Overall, the response rate was higher in those who received durvalumab (28.4%) than it was in those who were given placebo (16%; P
Excluding PD-L1–negative patients (≥1%), results were irrespective of PD-L1 25% or ≥25%. Moreover, all prespecified subgroups showed benefit.
OS data were published 10 months later, revealing superiority with durvalumab (66.3%) as compared with placebo (55.6%) at 1 year.2
In line with the 32% reduction in the risk of death seen with durvalumab, time to distant metastases or death was also improved with the agent (28.3 months) versus placebo (16.2 months).
In terms of safety, grade 3/4 adverse events (AEs) were observed in 30.5% and 26.1% of the experimental and control arms, respectively. The most common AE was pneumonia, and also led to the highest rate of treatment discontinuation.
"Rather than surveillance, waiting, and monitoring, we have an agent that improves survival,” said Gupta. “There's no doubt in my mind that this is one of the most significant changes in stage III disease in the last 20 years.”
For patients without EGFR
mutations who present with advanced disease and have a PD-L1 expression ≥50%, pembrolizumab (Keytruda) has become a suitable frontline option following its FDA approval in October 2016. However, many patients fail to meet this cutoff, stated Gupta, which may prevent them from receiving immunotherapy altogether.
The FDA is currently reviewing a supplemental biologics license application (sBLA) for pembrolizumab monotherapy for the frontline treatment of patients with locally advanced or metastatic nonsquamous or squamous NSCLC with a PD-L1 expression (tumor proportion score) level of ≥1% and no EGFR
genomic tumor aberrations. The agency is scheduled to make its decision on the sBLA by April 11, 2019.
Encouraging data from the phase III IMpower150 trial showed that patients with NSCLC can receive and benefit from a frontline immunotherapy-based combination. Data from the trial served as the basis for the FDA approval of atezolizumab (Tecentriq), with bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) for frontline use in patients with nonsquamous NSCLC and have no EGFR/ALK
In the trial, patients with stage IV or recurrent metastatic nonsquamous lung cancer (n = 1202) were randomized to receive atezolizumab plus carboplatin and paclitaxel (ACP; arm A; n = 402), ABCP (Arm B; n = 400), or bevacizumab with carboplatin and paclitaxel (BCP; arm C; n = 400).