Fast-progression (FP), hyper-progression (HPD) and early deaths (ED) in advanced non-small cell lung cancer (NSCLC) patients (pts) upon PD-(L)-1 blockade (IO).

Abstract

9107 Background: HPD was described in 13.8% of NSCLC pts upon single-agent IO and correlated with high metastatic burden and poor prognosis. Other progression (PD) patterns as FP and ED within 12 weeks have been reported respectively in 4.7% and 5.6% of atezolizumab treated NSCLC pts. Whether FP/ED and HPD are different or overlapping patterns is currently unknown. Methods: We analyzed FP, ED and HPD in a multicentric (8 centers) retrospective cohort of IO treated NSCLC pts (11/2012-04/2017). Eligibility criteria required 2 CT scans before and one after IO start. HPD was defined as RECIST v 1.1 PD at first CT scan and a variation per month of tumor growth rate (TGR upon IO – TGR before IO) > 50%. ED was defined as deaths due to disease PD within 12 wks of IO start. FP was defined as ≥ 50% increase in the sum of long diameters within 6 weeks (wks) from baseline. The associations between PD patterns and pts’ characteristics were performed using Fisher or t-student tests. Median overall survival (mOS) was estimated by Kaplan-Meier method and compared by log-rank test. Results: Out of 406 NSCLC pts, 46% were ≥65 years, 72% had non-squamous NSCLC, > 90% received single agent IO in ≥2 line. 56 (13.8%) were HPD by TGR analysis. Among 72 pts (18%) who performed a CT scan within 6 wks after IO start, 6 (8.3%) were FP. These 6 FP pts were also classified as HPD by TGR analysis, while the other 50 (89%) of 56 HPD pts were not FP. The rate of PD in ≥ 3 sites (54% vs 0%, p = 0.002), the rate of liver PD (62% vs 5%, p = 0.002), the baseline tumor burden (BTB) (mean 176± 26 mm vs 55 ± 6 mm, p < 0.0001) and the TGR upon IO (mean 439± 119% vs 216 ± 41%, p = 0.03) were significantly higher in FP pts compared to HPD pts who were not FP. At 4.4 months of median follow-up, FP pts had significantly worse mOS compared to HPD pts not FP [0.7 months (95% CI 0.6,0.8) vs 1.6 months (95% CI 1.1, 2.1); p = 0.02]. Of 406 IO treated pts, 46 (11%) were ED within 12 wks, and 21 (46%) of ED pts had also HPD by TGR analysis. Conclusions: FP and ED are not a surrogate of HPD. FP occurs in a small subgroup (11%) of HPD and correlates with more aggressive features (PD in ≥3 sites, liver-PD, high BTB, high TGR upon IO) and worse OS. ED within 12 wks overlapped with HPD for only 46% of pts.

The genomic characteristics of different progression patterns in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors

“…Ferrara et al (8) reported that patients who developed HPD within the first 6 weeks after treatment with a PD-1/PD-L1 inhibitor had an mOS of 3.4 months (n=23; 95% CI: 2.8-7.5 months). The mOS of FP patients was significantly shorter than that of HPD patients (0.7 vs. 1.6 months, P=0.02) (14). The mOS in our study appeared to be longer than those reported in previous studies, which may be due to our small sample size and the fact that a higher proportion of patients in our study received immunotherapy as a first-or second-line treatment.…”

“…Ferrara et al (14) reported that 6/6 FP patients and 21/46 ED patients were also classified as HPD based on TGR analysis. In our study, 3/6 FP patients and 2/3 ED patients were also classified as HPD, and 1 patient qualified for all 3 definitions (Figure 1C).…”

“…FP has been reported to occur in 11% of HPD patients, correlated with more aggressive features and worse survival. ED within 3 months was observed in 46% of HPD patients (14).…”

“…Inoue et al (12) defined ED as any death within 12 weeks after ICI treatment initiation. HPD is a new progression pattern, characterized by an accelerated tumor growth rate (TGR) after immunotherapy, defined as progression at the first evaluation and a >2-fold increase in the TGR compared with before ICI treatment (11,14). Although defined differentially, these progression patterns can display overlap.…”

Beyond First-Line Immunotherapy: Potential Therapeutic Strategies Based on Different Pattern Progressions: Oligo and Systemic Progression

“…A different clinical entity described is fast progression (FP), which is a progression within the first radiologic evaluation or no later than 12 weeks but not classifiable as HPD criteria [ 59 ]. According to some small evidence on the biological mechanisms, HPD is associated with a disimmunity, while FP is associated with primary resistance to immunotherapy [ 28 , 55 , 59 ].…”