Fast progression in patients treated with a checkpoint inhibitor (cpi) vs chemotherapy in OAK, a phase III trial of atezolizumab (atezo) vs docetaxel (doc) in 2L+ NSCLC
Authors: D.R. Gandara, M. Reck, S. Morris, A. Cardona, D. Mendus, M. Ballinger, A. Rittmeyer
Journal: Annals of Oncology (2018)

Background: Hyperprogressive disease (HPD), characterised by a rapid increase in tumour growth rate, has been recently reported in patients (pts) treated (tx) with CPI monotherapy and requires evaluation of pre-tx tumour growth rates. HPD is rare and has been associated with older age (>65 y; Champiat, CCR 2017), EGFR mutation (Kurzrock, Kato 2018) and poor OS. In the Phase III OAK study in 2L/3L NSCLC (n = 850), ITT OS was superior for atezo vs doc (mOS, 13.8 vs 9.6 mo; HR, 0.73). Here we examine fast progression (FP) as a surrogate for HPD, its relation to CPI vs chemo and association with efficacy according to pre-tx factors expected to be prognostic for FP, including early failure of the preceding tx. Methods: FP was defined as ≥ 50% increase in the SLD (per investigator) from baseline to first assessment (6 weeks) or death due to PD per investigator within 12 weeks without a post-tx scan. Baseline factors of pts with FP were compared for atezo vs doc to identify associations with a specific tx. OS was evaluated according to selected baseline factors, including early prior tx failure, LDH ≥225 units/L, SLD ≥80 mm and ≥3 metastatic sites. Results: The proportion of pts meeting FP criteria was similar between atezo and doc arms (n = 44 [10.4%] vs n = 41 [9.6%], respectively). Baseline factors for FP pts were similar across arms except for more males, non-smokers and fewer pts with early prior tx failure among atezo FP pts. Improved OS with atezo vs doc was seen in pts with early prior tx progression (median, 8.9 vs 6.2 mo), high LDH (median, 11 vs 8.9 mo), high SLD (median, 9.4 vs 6.9 mo), and ≥3 metastatic sites (median, 11.7 vs 8.6 mo).TableLBA1 Patient characteristics by FP status (ITT, N = 850)FPNon-FPAtezon=44Docn=41Atezon=381Docn=384Post-baseline status, n (%)SLD change ≥50% from baseline within 6 weeks20 (45)12 (29)N/AN/ADeath due to PD ≤ 12 weeks, without scan24 (55)29 (71)N/AN/ABaseline characteristics, n (%)Age, ≥65 y21 (48)20 (49)169 (44)187 (49)Male32 (73)21 (51)229 (60)238 (62)Non-smoker9 (20)4 (10)75 (20)68 (18)Non-squamousa | squamousa32 (73) | 12 (27)29 (71) | 12 (29)281 (74) | 100 (26)286 (74) | 98 (26)ECOG PS 0 | 19 (21) | 35 (80)12 (29) | 29 (71)146 (38) | 235 (62)148 (39) | 236 (62)EGFR positive3 (7)2 (5)39 (10)41 (11)PD-L1 positive (TC1/2/3 or IC1/2/3)25 (57)24 (59)216 (57)198 (52)PD-L1 negative (TC0 or IC0)19 (43)17 (42)161 (42)182 (47)Baseline LDH, ≥225 units/L24 (55)21 (51)185 (49)200 (52)Baseline SLD, ≥80 mm21 (48)18 (44)138 (36)153 (40)Metastatic sites at baseline, ≥332 (73)28 (68)206 (54)229 (60)Prior treatment failure, <180 days (i.e., early prior treatment failure)10 (31)15 (44)62 (22)53 (19)LDH, lactate dehydrogenase; N/A, not applicable; PD, progressive disease; SLD, sum of longest diameters. NCT02008227 aPer electronic case report form. Open table in a new tab LDH, lactate dehydrogenase; N/A, not applicable; PD, progressive disease; SLD, sum of longest diameters. NCT02008227 aPer electronic case report form. Conclusions: The proportions of FP pts in atezo and doc arms were similar, suggesting that rapid post-baseline progression is not specific to anti–PD-L1 tx. A consistent benefit of tx with atezo vs doc was seen across subgroups defined by baseline factors associated with aggressive disease. Editorial acknowledgement: Chris Lum, PhD of Health Interactions, Inc. Clinical trial identification: NCT02008227. Legal entity responsible for the study: F. Hoffmann-La Roche, Ltd. Funding: F. Hoffmann-La Roche, Ltd. Disclosure: D.R. Gandara: Consulting/advisory role: Genentech, AZ, Merck; Supported/contracted research/grant: Genentech; Support of parent study and funding of editorial support: F.Hoffmann-La Roche. M. Reck: Consulting/advisory role, speakers bureau: F. Hoffmann-La Roche, Lilly, BI, AstraZeneca, MSD, BMS, Merck, Novartis, Pfizer, Celgene; Support of parent study and funding of editorial support: F. Hoffmann-La Roche. S. Morris: Employee and stock: Roche; Support of parent study and funding of editorial support: F. Hoffmann-La Roche. A. Cardona: Employee: Roche; Support of parent study and funding of editorial support: F. Hoffman-La Roche. D. Mendus: Employee: Genentech/Roche; Support of parent study and funding of editorial support: F. Hoffmann-La Roche. M. Ballinger: Employee: Genentech/Roche; Stock: Roche; Support of parent study and funding of editorial support: F. Hoffmann-La Roche. A. Rittmeyer: Speakers bureau: Lilly, BMS, MSD, Roche/Genentech; Consulting/advisory role: Lilly, BMS, Boehringer Ingelheim, AstraZeneca, MSD, Pfizer, Roche/Genentech, AbbVie; Support of parent study and funding of editorial support: F. Hoffmann-La Roche.