ESMO Immuno-Oncology 2018: OAK Trial: Fast Progression in Patients With NSCLC Treated With Atezolizumab vs Chemotherapy
Overall survival (OS) was improved across all subgroups of patients with non–small cell lung cancer (NSCLC) who received atezolizumab (Tecentriq) compared with chemotherapy, including poor prognostic factors that were evaluated in an analysis of data from the OAK trial. Additionally, this study observed no evidence of quicker disease progression with the programmed death- igand 1 (PD-L1) monoclonal antibody atezolizumab compared to chemotherapy, suggesting this may not be a phenomenon solely related to cancer immunotherapies as has been previously suggested. These findings were presented by Gandara et al at the European Society for Medical Oncology (ESMO) Immuno-Oncology Congress 2018 (Abstract LBA1).
David R. Gandara, MD, of the University of California, Davis Comprehensive Cancer Center, presented data on behalf of colleagues from a study designed to determine whether fast progression was a factor in patients treated with atezolizumab in the OAK trial.
Fast Progression and Hyperprogressive Disease
This analysis used fast progression—defined as an increase of 50% or more in the sum of the longest diameters of tumors (SLD) from baseline to first assessment at 6 weeks or upon death due to disease progression (PD)—as evaluated by the investigator within 12 weeks of treatment without a posttreatment scan.
Fast progression (FP) was used as a surrogate for the rare phenomenon hyperprogressive disease (HPD), which has emerged in some patients treated with immunotherapy in clinical trials. HPD is characterized by rapid tumor growth rate and accelerated disease progression following PD-L1 checkpoint inhibitor therapy. Assessment of HPD requires an evaluation of pretreatment tumor growth rates, therefore the surrogate of fast progression was used in this study. HPD has been associated with age more than 65 years and epidermal growth factor receptor (EGFR) mutation, and is characterized by a poorer OS.
OAK
The phase III OAK study compared checkpoint inhibition with atezolizumab vs chemotherapy with docetaxel in the second- and third-line settings in 850 patients with NSCLC. In OAK, superior median OS of 13.8 months was observed with atezolizumab compared to 9.6 months with docetaxel (hazard ratio [HR] = 0.73) in the intent to treat (ITT) population.
In order to examine fast progression as a surrogate for HPD, the investigators first categorized fast progressors in the two treatment arms. Similar numbers of patients in both treatment arms met the criteria for fast progression and/or HPD.
The investigators then reviewed the baseline characteristics of FP and non-FP patients in OAK for selected pretreatment factors that could be correlated with fast progression for a comparison between the atezolizumab and docetaxel treatment arms. The OS per arm was evaluated according the selected factors, which included early treatment failure with the previous therapy, lactate dehydrogenase (LDH) levels ≥ 225 units/L, SLD ≥ 80 mm, and ≥ 3 metastatic sites.
As noted, the proportion of patients having the selected baseline factors for fast progression was equivalent in the two treatment arms; 44 (10.4%) patients treated with atezolizumab compared to 41 (9.6%) patients treated with docetaxel met the criteria for fast progression. The overall baseline characteristics were generally similar between arms, except the atezolizumab arm contained more male patients, more nonsmokers, and fewer (10 [31%] vs 15 [44%], atezolizumab vs docetaxel) patients that had demonstrated early failure to prior treatment. In both arms, the majority of patients had been heavily pretreated.
Regarding the cohort of patients having baseline indicators for fast progression, 24 (55%) patients in the atezolizumab arm vs 21 (51%) patients in the docetaxel arm had baseline LDH ≥ 225 units/mL, and 21 (48%) vs 18 (44%) patients had baseline SLD ≥ 80 mm, respectively. In the respective cohorts, 32 (73%) vs 28 (68%) patients had 3 or more metastatic sites at baseline and 10 (31%) vs 15 (44%) had experienced failure to their previous treatment within 180 days of initiation.
In addition, 21 (48%) vs 20 (49%) patients were aged ≥ 65 years, and 3 (7%) vs 2 (5%) patients were EGFR-mutation positive, therefore, having factors associated with HPD. Another variable associated with poor prognosis is PD-L1 expression on tumor or immune cells; PD-L1 was expressed in 25 (57%) patients in the atezolizumab arm vs 24 (59%) of patients on docetaxel, and PD-L1 was as not expressed in 19 (43%) vs 17 (42%) of patients, respectively.
Findings
An evaluation of OS according to each pretreatment risk factor for fast progression indicated median OS was improved overall with atezolizumab. Median OS was 8.9 months with atezolizumab vs 6.2 months with docetaxel in patients showing early progression on prior treatment. Patients with high baseline LDH levels had median OS of 11 vs 8.9 months. Median OS was 9.4 vs 6.9 months in patients with high SLD, and patients with ≥ 3 metastatic sites demonstrated median OS of 11.7 vs 8.6 months with atezolizumab vs docetaxel, respectively.
Twenty (45%) patients receiving atezolizumab and 12 (29%) patients on docetaxel demonstrated an SLD change ≥ 50% from baseline within 6 weeks. In the respective treatment arms, 24 (55%) vs 29 (71%) patients died due to disease progression within 12 or fewer weeks of treatment.
Conclusions
Equivalent proportions of patients in each treatment arm experienced fast progression, suggesting that rapid postbaseline progression is not specific to atezolizumab or anti–PD-L1 therapy in general. The superior benefit with atezolizumab over docetaxel was consistent across all subgroups defined by baseline factors associated with aggressive disease, according to the investigators. Further study is required to understand the underlying biological mechanisms of why certain patients experience tumor growth acceleration, as well as consistent means to measure this phenomenon.
Disclosure: The study authors’ full disclosures can be found at academic.oup.com.
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