Updated survival and biomarker analyses of a randomized phase II study of atezolizumab vs. docetaxel in 2L/3L NSCLC (POPLAR)

Background:

Atezolizumab (atezo, MPDL3280A), a humanized engineered mAb, is the first anti-PD-L1 agent to show improved OS vs. docetaxel (doc) in NSCLC. These results correlate with PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC) and have shown improvement over time as reflected by the continued late separation of OS curves.

Methods:

Pts were randomized to receive atezo 1200 mg IV q3w or doc 75 mg/m2 IV q3w. Tumors were prospectively evaluated for PD-L1 expression using the SP142 IHC assay and scored from low to high (0 – 3). Gene expression was analyzed using a Fluidigm platform. The primary endpoint was OS and the primary analysis included 173 events among 287 randomized pts (event/patient ratio [EPR] 60%; min follow up 13 mo). Here we present data as of Dec 1, 2015 with a min follow up of 20 mo.

Results:

With longer follow up and 200 events (EPR 70%) further separation in survival curves and improvement in OS HR were seen for atezo over doc for ITT (HR 0.69, 95% CI 0.52 – 0.92) and across PD-L1 and histology subgroups (Table). Longer mDOR was seen for atezo vs. doc (18.6 vs. 7.2 mo). Improved OS with atezo over doc correlated with high tumor expression of Teff/IFNγ-associated genes (unstratified HR 0.52, 95% CI 0.32 – 0.83). Atezo continues to have a tolerable safety profile distinct from doc.

	OS
	Atezo		Doc		HR a	PValue b
	n	Median, mo	n	Median, mo	95% CI
ITT	144	12.6	143	9.7	0.69 0.52 – 0.92	.011
TC3 or IC3	24	NRC	23	11.1	0.45 0.22 – 0.95	.033
TC2/3 or IC2/3	50	15.1	55	7.4	0.50 0.31 – 0.80	.003
TC1/2/3 or IC1/2/3	93	15.1	102	9.2	0.59 0.41 – 0.83	.003
TC0 and IC0	51	9.7	41	9.7	0.88 0.55 – 1.42	.601
Squamous	49	10.1	48	8.6	0.66 0.41 – 1.05	.075
Nonsquamous	95	14.8	95	10.9	0.69 0.49 – 0.98	.039
aStratified for ITT, unstratified for subgroups bDescriptive only cNot reached

Conclusions:

Extended follow up reveals further separation late in OS curves and increased benefit with atezo monotherapy vs. doc. Relative to the primary analysis, OS benefit is improved in ITT and PD-L1 subgroups, including TC0 and IC0, and in pts with squamous NSCLC. In addition, PD-L1 expression measured by IHC and the tumor Teff/IFNγ gene signature, which reflects pre-existing immunity, can identify pts most likely to benefit from atezo.