Front-line atezolizumab improves overall survival in advanced NSCLC
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NATIONAL HARBOR, Md. — Patients who received atezolizumab as first-line monotherapy for metastatic non-small-cell lung cancer showed significant improvement in overall survival, according to phase 3 interim overall survival analysis data of the IMpower 110 trial presented at Society for Immunotherapy of Cancer Annual Meeting.
The study met its primary end point of significantly improved overall survival for patients whose tumors expressed higher levels of PD-L1 and received atezolizumab (Tecentriq, Genentech) monotherapy compared with platinum-based chemotherapy.
“There is a population of patients with NSCLC that does not need chemotherapy immediately,” Giuseppe Giaccone, MD, PhD, assistant professor of medicine at Weill Cornell Medicine and associate director for clinical research at the Sandra and Edward Meyer Cancer Center, told HemOnc Today. Gianccone, one of the study’s co-authors, said their aim is to displace chemotherapy as first-line treatment for the population of patients with NSCLC who have high PD-L1 expression.
“Merck has already done this with pembroliziumab (Keytruda), and now atezolizumab is showing it can do the same with a very similar result,” he said.
The IMpower 110 trial enrolled 572 patients with stage IV squamous or nonsquamous NSCLC who did not have previous platinum-based chemotherapy. Study patients had 1 PD-L1 expression on tumor cells (TCs) or tumor-infiltrating immune cells (ICs). All patients had measurable disease according to RECIST version 1.1 criteria and an ECOG performance status of 0 to 1.
Study patients were randomly assigned in a 1:1 fashion to receive IV atezolizumab 1,200 mg every three weeks (Arm A) or platinum-based chemotherapy in four or six 21-day cycles (Arm B).
Arm B patients with nonsquamous NSCLC received cisplatin 75 mg/m2 or IV carboplatin AUC 6 plus IV pemetrexed 500 mg/m2 every three weeks; Arm B patients with squamous NSCLC received cisplatin 75 mg/m2 plus gemcitabine 1,250 mg/m2 or IV carboplatin AUC 5 plus IV gemcitabine 1000 mg/m2 every three weeks.
Results were risk stratified according to sex, ECOG performance status, histology and tumor PD-L1 expression (TC1/2/3 and any IC vs TC0 and IC1/2/3). The primary end point of OS was tested hierarchically in the wild-type (EGFR/ALK-negative) population (TC3 or IC3 then TC2/3 or IC2/3 then TC1/2/3 or IC1/2/3).
The three primary efficacy populations included 554 TC1/2/3 or IC1/2/3 wild-type patients, 328 TC2/3 or IC2/3 wild-type patients and 205 TC3 or IC3 wild-type patients.
The median study follow-up was 15.7 months (range, 0-35) in TC3 or IC2 wild-type patients.
Atezolizumab monotherapy improved median OS by 7.1 months (HR = 0.59) in the TC3 and IC3 WT population compared with platinum-based chemotherapy. Gianconne told the audience that, for the most part, higher expressers of TC/IC had longer survival and better response rates to atezolizumab monotherapy.
Gianconne said the median survival improvements are tremendous by lung cancer’s standards and rival the benefits previously seen with first-line pembrolizumab.
The safety population included 286 patients in Arm A and 263 patients in Arm B. Treatment-related adverse events occurred 60.5% of patients in Arm A and 85.2% of patients in Arm B. Serious (grade 3 or 4) treatment-related adverse events occurred in 12.9% of patients in Arm A and 44.1% of patients in Arm B.
“It will be interesting to see how the results of this study impact clinical practice because it will use a different antibody and a different method for selection of patients that requires a platform that examines both immune cells and tumor cells,” Gianconne said.
“Pathologist will have to learn how to do this, and there will be leaning curve for them because not all of these assays are straightforward,” he added. “This could be a limiting factor for uptake of this treatment unless a solution is created that allows pathologists to do patient selection by bringing together both platforms.” – by Drew Amorosi
Reference: Herbst R, et al. Abstract O81. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 7-10, 2019; National Harbor, MD.
Disclosures: This study was funded by Hoffmann-La Roche.
Perspective
Back to TopTimothy F. Burns, MD, PhD
The results of the interim OS analysis of the phase 3 IMpower 110 trial further support a role for anti-PD-1/PD-L1 monotherapy in the first-line setting for patients with NSCLC whose tumors express high levels of PD-L1. Previous studies established monotherapy with the anti-PD-1 agent pembrolizumab as a standard of care in the first-line setting for patients with PD-L1 expression greater than 50%. The current study supports the use of the anti-PD-L1 agent atezolizumab as a standard-of-care option in the first-line setting among patients with NSCLC whose tumors express high levels of PD-L1.
The previous pembrolizumab monotherapy trials and the current study included similar populations and allowed patients with both squamous and nonsquamous treatment-naive NSCLC. Researchers also observed comparable improvements in OS in their respective PD-L1-high populations. However, whether these are the same patient populations is unclear.
Whereas high PD-L1 expression was defined as greater than 50% PD-L1 expression in the tumor for the pembrolizumab studies, the IMpower 110 trial defined high PD-L1 as either greater than 50% PD-L1 expression in the tumor (TC3) or greater than 10% PD-L1 expression in immune cells (IC3). Further, the SP142 PD-L1 immunohistochemistry assay that was used for the primary analysis has been found to be discordant and less predictive for response than other standard PD-L1 assays. Thus, the high PD-L1 expressors in these trials likely represent distinct but partially overlapping populations. Importantly, the future presentation of the SP263 and 22C3 PD-L1 immunohistochemical analyses should further clarify how distinct these populations are.
This study also raises several important questions about who should receive atezolizumab and whether we can further refine this population. Analysis of key subgroups in the TC3 or IC3 population suggested different benefits from atezolizumab. Like previous studies, women appeared to benefit less than men from anti-PD-1/PD-L1 monotherapy.
These findings reinforce the need for preclinical and eventual clinical studies to understand the biology underpinnings of this sex difference and develop therapies to improve outcomes among women. In addition, never-smokers failed to benefit from atezolizumab compared with chemotherapy, although they appeared to benefit from chemoimmunotherapy.
Whether molecularly defined subtypes may further identify those patients who may benefit from therapy hopefully will be examined in the future.
Of note, EGFR-mutant or ALK translocation-positive patients (n = 18) were not excluded from this trial; however, data have been presented only for the wild-type population. Of greater potential interest would be the frequency and negative predictive value of candidate biomarkers for lack of response, such as STK11 or KEAP1 alterations.
UPMC Hillman Cancer Center
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