September 2015, Vol. 2, No. 5
Anti–PD-L1 Alone or Combined with Chemotherapy for NSCLC
Preliminary clinical trials suggest that the investigational programmed death-1 ligand 1 (PD-L1) inhibitor atezolizumab has excellent single-agent activity and also can be safely combined with platinum-based chemotherapy for the treatment of non–small cell lung cancer (NSCLC). Atezolizumab is 1 of 3 anti–PD-L1 agents in development; none is currently approved by the FDA. Phase 3 trials evaluating frontline therapy with atezolizumab in combination with chemotherapy are under way in NSCLC.
Atezolizumab (formerly MPDL3280A), an investigational anti–PD-L1 antibody, has shown promise in PD-L1–selected patients with NSCLC. As a single agent, atezolizumab had excellent response rates in both chemotherapy-naive and previously treated patients with metastatic NSCLC in the phase 2 FIR study. Levels of PD-L1 expression were correlated with response.
“This is the first dedicated clinical experience [with atezolizumab] in NSCLC. FIR was a nonrandomized trial of newly diagnosed metastatic NSCLC. We took all comers and saw responses in both chemotherapy-naive and pretreated patients, so the results are applicable to any patient with advanced NSCLC,” explained lead author David Spigel, MD, Sarah Cannon Research Institute, Nashville, TN.
The study was designed to be enriched for PD-L1 expression. More than 1000 patients were screened for PD-L1 expression in both archived and fresh tumor specimens by expression on immune cells (IC) or tumor cells (TC) scored as IC 0, 1, 2, or 3, and TC 0, 1, 2, or 3.
Two hundred five patients were selected for the trial because they tested at high levels of PD-L1 expression: TC2/3 and/or IC2/3. Of these, 137 patients were enrolled and treated with atezolizumab 1200 mg intravenously every 3 weeks. Median age was 66 years, and 58% were male.
There were 3 cohorts. Cohort 1 included 31 chemotherapy-naive patients; cohort 2, 92 patients with at least 1 prior line of chemotherapy and no brain metastases; and cohort 3, 13 patients with asymptomatic brain metastases treated with at least 2 prior lines of therapy.
The highest overall response rates (ORRs) were observed in the highest PD-L1 expressors (TC3 or IC3). The ORRs were 26% in cohort 1, 16% in cohort 2, and 23% in cohort 3. Among TC3 or IC3 patients, the response rate was 29% in cohort 1, 24% in cohort 2, and 25% in cohort 3. The median duration of response had not yet been reached at the time of ASCO.
Median progression-free survival (PFS) was 4.5 months in cohort 1, 2.7 months in cohort 2, and 2.3 months in cohort 3. Among TC3 or IC3 patients, median PFS was 5.4 months for cohort 1, 4.1 months for cohort 2, and 2.3 months for cohort 3.
The adverse event profile of atezolizumab was similar in all 3 cohorts. Two-thirds of patients had treatment-related adverse events, most commonly fatigue (26%), nausea (15%), and decreased appetite (14%). Treatment-related grade 3/4 adverse events were reported in 15% of patients; 1 treatment-related death occurred due to constrictive pericarditis.
PD-L1 as Biomarker?
Spigel said that the study enrolled only patients who expressed a specific level of PD-L1, enriching the population for the trial. However, only 20% of the 1000 NSCLC patients screened met these criteria.
“There is a catch. We know some non–PD-L1 expressors respond to atezolizumab, so this enriched population leaves out some people who could benefit,” he noted.
PD-L1 may not be the best biomarker to select for benefit from this agent. Other biomarkers are being studied, but so far none has uniformly showed that it is the best way to identify responders. Other studies have shown that PD-L1 status does not enrich for response, so the usefulness of PD-L1 as a biomarker for treatment selection remains uncertain (Abstract 8028).
Atezolizumab in Combination with Chemotherapy
A second study showed encouraging activity with the combination of atezolizumab plus 1 of 3 different platinum-based chemotherapy doublets commonly used to treat patients with advanced NSCLC. Tumor shrinkage was observed in two-thirds of patients (67%) enrolled in the trial regardless of the level of PD-L1 expression. The combination was well tolerated throughout treatment, including maintenance therapy, and can be safely administered to patients with no unexpected toxicities.
The most frequent adverse events were those seen with chemotherapy, including nausea, fatigue, and constipation. No autoimmune or renal toxicity was reported.
“We are encouraged that a high proportion of people responded to combined treatment…in this early lung cancer study. This indicates that combinations may provide a way to extend the benefits of atezolizumab to a wider range of people, including those with low levels of PD-L1 expression,” stated Sandra Horning, MD, in a news release from Roche. Horning is Chief Medical Officer and Head of Global Clinical Product Development for Roche.
The multicenter, multiarm phase 1b study evaluated the safety and efficacy of atezolizumab plus platinum-based doublet chemotherapy in patients with histologically or cytologically documented stage IIIB (ineligible for definitive chemoradiotherapy), stage IV, or recurrent NSCLC. The study included 30 patients, 20 of whom had a response according to RECIST guidelines for tumor shrinkage. About 80% had nonsquamous histology (the most common form of NSCLC), 14% were current smokers, 70% were former smokers, and 16% were never-smokers.
Patients received 6 cycles of treatment unless progressive disease or unexpected toxicity developed; this was followed by atezolizumab maintenance therapy. Atezolizumab could be continued if there was disease progression but also evidence of clinical benefit (as has been seen with other immunotherapies).
ORR was 67%; this included complete responses in 3 patients (10%) and partial responses in 17 patients (57%). Stable disease was observed in 6 patients (20%), and progressive disease in 3 patients (10%). One patient died and was not included in response assessment (Abstract 8030).
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