Predictive value of baseline clinicopathological factors in non-small cell lung cancer (NSCLC) patients on checkpoint inhibitors (CPI).

e14119 Background: Tumor PD-L1 expression and tumor mutational burden currently serve as primary predictive markers for CPI efficacy in NSCLC. However, these markers are imperfect due to tumor heterogeneity, changes over time, and lab variations. These challenges highlight importance of developing dynamic, readily available predictive biomarkers. We evaluated predictive value of pre-treatment Neutrophil-to-Lymphocyte Ratio (NLR), smoking history (SH), body mass index (BMI) and smoking intensity (SI) in NSCLC patients (pts) on CPIs. Methods: Retrospective analysis of NSCLC pts treated with CPIs July 2015 to November 2017. Pt demographics, tumor PD-L1 status positive (pos) or negative (neg) (PD-L1 &gt; 0% or 0% respectively), SH, SI (heavy smokers (HS) or non-heavy smokers (NHS) [ = / &gt; 20 pack-year (PY) and &lt; 20 PY respectively], NLR and BMI high or low based on cutoffs of 5 and 25, respectively were captured. Disease Control Rate (DCR) was defined as objective response or stable disease per RECIST 1.1 at 3 months (m). Median overall survival (OS) and time to progression (TTP) were calculated. Fisher’s exact test and chi-square test were used to compare DCR for each group. Kaplan-Meier curves were used to estimate OS and TTP for each factor. Results: 140 pts were included. NLR was associated with DCR, OS, and TTP. 62/90 (68.9%) pts in the low NLR group and 18/47 (38.3%) in the high NLR group had DCR (p &lt; 0.0006). Median OS for low NLR was 15 m (95% CI: 11.75, 22.25) vs. 5.25 m for high NLR (95% CI: 2.75, 9.75) (p &lt; 0.0005). Median TTP for low NLR was 8 m (95% CI: 6.00, 11.25) vs 3 m for the high (95% CI, 2.00, 4.00) (p &lt; 0.0001). SH was not associated with DCR or survival, but was predictive of TTP. SI was predictive of DCR, but not OS or TTP. 65/100 (65.0%) HS and 15/34 (44.1%) NHS had DCR (p &lt; 0.0320). BMI and PD-L1 (n = 55) were not associated with any outcome. There was association between high BMI and low NLR (P &lt; 0.0381). There were no other associations between factors. Conclusions: NLR &lt; 5 was associated with improvement in all measures of outcome while smoking was associated with some. Neither BMI nor PD-L1 were predictive of any outcome. A score incorporating NLR and smoking status may be beneficial in choosing patients for CPIs. </jats:p

Acquired resistance to PD-1 blockade in NSCLC.

9621 Background: Although durability is the trademark characteristic of response to PD-1 blockade, acquired resistance can occur. The frequency, patterns, and survival outcomes of patients with acquired resistance to PD-1 blockade are unknown. Methods: All patients with NSCLC treated with PD-1 blockade at MSKCC were examined. Acquired resistance was defined as initial CR/PR (by RECIST) followed by progression/death. Oligo vs systemic patterns of acquired resistance were defined as progression in ≤ 2 sites of disease or ≥ 3 sites of disease, respectively. Results: Of 1201 patients treated with PD-1 blockade, 243 (20%) achieved initial response and 189 (78%, 95% CI 72-83%) eventually developed acquired resistance (AR). Onset of AR was variable and decreased with longer duration of response (53% within 1 year, 37% 1-2 years, 10% &gt; 2 years). Patients with PD-L1 expression &lt; 50% and TMB &lt; 8mut/Mb were more likely to develop resistance compared those with PD-L1 expression ≥50% and TMB ≥8mut/Mb (OR 5.5, p = 0.02). Unlike organ sites of primary refractory disease, AR commonly occurred in lymph nodes (41%) and infrequently in the liver (6%). Patterns of AR were most commonly oligo rather than systemic (79/141 [56%], 39/141 [28%]); some patients died without radiographic progression (23/141 [16%]). Oligo-AR occurred later (median onset 13 vs 5.6 mo) and associated with improved post-progression survival (median OS 55.2 vs 9.2 mo, HR 6.0, p &lt; 0.001) compared to systemic-AR. Post-progression survival was highest in patients with AR compared to those with initial SD or PD to PD-1 blockade (median 18.9 vs 12.5 vs 4.4, p &lt; 0.001). Of 49 patients treated initially with locally-directed therapy for AR, 28 (57%) remain alive and systemic therapy-free. Conclusions: Acquired resistance to PD-1 blockade is common in NSCLC. Risk of acquired resistance is lower in biomarker-enriched patients and with increased duration of response. Patterns of acquired resistance is commonly oligo in nature, which is amenable to locally-directed therapy and can be associated with improved survival. Differences in organ-site distribution and post-progression survival suggest distinct biology associated with acquired resistance vs primary refractory disease. </jats:p

Outcomes of single-agent PD-(L)-1 versus combination with chemotherapy in patients with PD-L1-high (≥ 50%) lung cancer.

9052 Background: Single agent PD-(L)-1 blockade (IO) and PD-(L)-1 blockade combined with chemotherapy (ChemoIO) are both standard first-line treatments for patients with PD-L1-high (≥ 50%) metastatic non-small cell lung cancer (NSCLC). These regimens have not been compared prospectively, so comparative effectiveness is unclear. It is also unknown if clinical and molecular tumor characteristics differentially associate with benefit to IO vs ChemoIO in patients with NSCLC with high PD-L1 tumor expression. Methods: All patients with metastatic NSCLC treated with IO or ChemoIO at two institutions (Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute) were reviewed. Patients with EGFR or ALK alterations, PD-L1 expression &lt; 50%, treated with IO or ChemoIO in &gt; 1st line setting were excluded. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were compared between the IO vs ChemoIO groups and association with clinical, pathologic, and molecular features was examined. To account for NGS panel differences, tumor mutational burden (TMB) values were harmonized using a z-score conversion as previously described (Vokes et al, 2019). Results: Of 639 patients with stage IV EGFR/ ALK wild-type NSCLC and PD-L1 ≥50% treated in the 1st line setting, 504 received IO and 135 received ChemoIO. Baseline ECOG performance status (p = 0.3), median PD-L1 % (p &gt; 0.9) and TMB (p = 0.2) were similar between the IO and ChemoIO groups. For patients receiving IO vs ChemoIO, there was no significant difference in OS (HR 0.8, 95% CI 0.6 to 1.08; p = 0.2). Median PFS was shorter (HR 0.7, 95% CI 0.6 to 0.9; p = 0.004) and ORR was lower (40% IO vs 55% ChemoIO, p = 0.002) in the IO group. Among patients with durable responses (&gt; 6 months), never smokers were less common in the IO group (6% vs 18%, p &lt; 0.001), but there was no difference in PD-L1 expression, TMB, or mutational ( KRAS, STK11, or KEAP1) profile to suggest differential predictors of benefit to IO or ChemoIO. Conclusions: In patients with PD-L1 high NSCLC, there was no survival benefit associated with the addition of chemotherapy to IO. There were also no clear differences in PD-L1 expression or molecular features associated with durable response to IO vs ChemoIO. These findings have implications for treatment selection in this population. </jats:p

Long-term responders to PD-1 blockade in patients with advanced non-small cell lung cancer (NSCLC).

9549 Background: Long-term response – the plateau of the survival curve – is the transcendent benefit from PD-1 blockade. However, only a subset of responses achieve substantial durability. The frequency, characteristics, and predictors of long-term responders (LTR) to PD-1 blockade are not well known and may differ from short-term responders (STR). Methods: Patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy from two institutions (MSK and DFCI) were examined. Responses were assessed by RECIST. LTR was defined as PR/CR lasting ≥ 24 months. STR was defined as PR/CR lasting &lt; 12 months. Comparisons were also made to patients with progressive disease (PD). PD-L1 expression was assessed by IHC. TMB was assessed by targeted NGS; high TMB was defined as ≥ median of the cohort. A subset had detailed molecular profiling by MSK-IMPACT. Fisher’s exact and Mann-Whitney U tests were used to compare features, and the log-rank test was used to compare survival. Results: Of 2318 patients (MSK n = 1536, DFCI n = 782), 126 (5.4%, 95% CI 4.6-6.4%) achieved LTR, with similar rates in both cohorts. STR occurred in 139 (6%). Overall survival was longer in LTR compared to STR (median NR vs 19.6 months, HR 0.07, p &lt; 0.001). LTR had deeper responses compared to STR (median best overall response -69% vs -46%, p &lt; 0.001). Patients with LTR were younger ( &lt; 65 years old) and had increased TMB (≥ median mut/Mb) compared to both STR and PD (p = 0.006, p = 0.03; p &lt; 0.001, p &lt; 0.001). The rate of LTR was enriched among patients with both high TMB/high PD-L1 compared to those with low TMB/low PD-L1 (9% vs 1%, OR 9.2, p &lt; 0.001), while STR was similar in both groups (7% vs 6%). 2% of patients with sensitizing EGFR mutations (n = 243) achieved LTR. Loss of function variants in ARID1A (14% vs 2%), PTEN (8% vs 0%), and KEAP1 (12% vs 2%) were enriched in LTR compared to STR (p &lt; 0.05 for each). Among patients with KRAS mutations, the rate of LTR was higher in those with co-mutation with TP53 compared to STK11 (11% vs 2%, p = 0.01). Conclusions: Long-term response (LTR, ongoing response ≥ 24 months) to PD-1 blockade is an uncommon but profound clinical outcome in metastatic lung cancers. Younger age and high TMB correlate with LTR; the combination of high TMB/high PD-L1 enriches for LTR but not STR. Features predicting long term response may be distinct from those predicting initial response. </jats:p