First-line Platinum Doublet Chemotherapy Research Articles

Evaluation of Real-World Tumor Response Derived From Electronic Health Record Data Sources: A Feasibility Analysis in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Chemotherapy.

Real-world data (RWD) holds promise for ascribing a real-world (rw) outcome to a drug intervention; however, ascertaining rw-response to treatment from RWD can be challenging. Friends of Cancer Research formed a collaboration to assess available data attributes related to rw-response across RWD sources to inform methods for capturing, defining, and evaluating rw-response. This retrospective noninterventional (observational) study included seven electronic health record data companies (data providers) providing summary-level deidentified data from 200 patients diagnosed with metastatic non-small cell lung cancer (mNSCLC) and treated with first-line platinum doublet chemotherapy following a common protocol. Data providers reviewed the availability and frequency of data components to assess rw-response (ie, images, radiology imaging reports, and clinician response assessments). A common protocol was used to assess and report rw-response end points, including rw-response rate (rwRR), rw-duration of response (rwDOR), and the association of rw-response with rw-overall survival (rwOS), rw-time to treatment discontinuation (rwTTD), and rw-time to next treatment (rwTTNT). The availability and timing of clinician assessments was relatively consistent across data sets in contrast to images and image reports. Real-world response was analyzed using clinician response assessments (median proportion of patients evaluable, 77.5%), which had the highest consistency in the timing of assessments. Relative consistency was observed across data sets for rwRR (median 46.5%), as well as the median and directionality of rwOS, rwTTD, and rwTTNT. There was variability in rwDOR across data sets. This collaborative effort demonstrated the feasibility of aligning disparate data sources to evaluate rw-response end points using clinician-documented responses in patients with mNSCLC. Heterogeneity exists in the availability of data components to assess response and related rw-end points, and further work is needed to inform drug effectiveness evaluation within RWD sources.

Geriatric Nutritional Risk Index as Prognostic Marker for Elderly Patients With Small Cell Lung Cancer.

The Geriatric Nutritional Risk Index (GNRI) indicates nutritional status based on serum albumin concentration and ideal body weight. Pretreatment GNRI has been suggested as a prognostic factor for various malignancies. However, little is known about the clinical value of GNRI for small-cell lung cancer (SCLC), especially in elderly patients. We retrospectively analyzed 53 elderly (≥71) patients with extensive-disease (ED) SCLC treated with first-line platinum-doublet chemotherapy in relation to the pretreatment GNRI level in a real-world setting. Thirty-six patients with a low GNRI (<92) had statistically poorer progression-free survival (PFS) and overall survival (OS) than 17 patients with a high GNRI (≥92) (median PFS=80 days vs. 133 days, respectively; p=0.002; median OS=123 days vs. 274 days, respectively; p=0.004). In a multivariate analysis, a low GNRI was also an independent poor prognostic factor for PFS [hazard ratio (HR)=0.396; 95% confidence interval (CI)=0.199-0.789; p=0.008] and OS (HR=0.295; 95%CI=0.143-0.608; p<0.001). The GNRI might be a predictive and prognostic marker in elderly patients with ED-SCLC treated with platinum-doublet chemotherapy.

Serum CYFRA 21-1 Level as a Prognostic Marker for Extensive Disease Small Cell Lung Cancer.

Pretreatment serum cytokeratin 19 fragment (CYFRA21-1) level predicts outcomes in patients with non-small cell lung cancer; however, little is known about the clinical value of serum CYFRA21-1 level in patients with small cell lung cancer (SCLC). The aim of this study was to evaluate the prognostic value of pretreatment serum CYFRA21-1 level in patients with extensive disease (ED)-SCLC treated using platinum-doublet chemotherapy. We retrospectively analyzed the pretreatment serum CYFRA21-1 levels of patients with ED-SCLC who were treated using first-line platinum-doublet chemotherapy. A total of 98 patients were analyzed. The patients with a high CYFRA21-1 level (≥7.0 ng/ml) (n=29) had significantly shorter progression-free survival (PFS) and overall survival (OS) than the patients with low CYFRA21-1 levels (n=67) [median PFS=118 days vs. 125 days, respectively (p=0.018); median OS=213 days vs. 295 days, respectively (p=0.046)]. In addition, high CYFRA21-1 level was associated with a high refractory relapse rate. Serum CYFRA21-1 level may be a prognostic marker for patients with ED-SCLC treated with platinum-doublet chemotherapy.

Cost-effectiveness of camrelizumab combined with chemotherapy in the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma in China

ObjectiveThis study aimed to investigate the cost-effectiveness of adding Chinese-developed anti-PD-1 antibody camrelizumab to first-line platinum-doublet chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma (L/M NPC) from the perspective...

Clinical outcomes of Epstein-Barr virus (EBV)-associated metastatic and locally advanced unresectable gastric cancers (GCs) in patients receiving first-line fluoropyrimidine and platinum (FP) doublet chemotherapy.

Epstein-Barr virus-associated gastric cancer (EBVaGC) is a distinct molecular subgroup showing excellent outcomes after surgery for localized disease. Prominent immune cell infiltration in EBVaGC reflects the immunogenicity of Epstein-Barr virus (EBV) and, as suggested by some investigators, responsiveness to immune checkpoint inhibitors in the palliative setting. However, few data are available on the prevalence, clinical characteristics, and prognosis of EBVaGC patients receiving palliative cytotoxic chemotherapy. In this retrospective study, we identified 1061 patients with metastatic, recurrent, or locally advanced unresectable gastric cancer (GC) who started first-line fluoropyrimidine/platinum (FP) doublet chemotherapy with or without trastuzumab from January 2015 to August 2018. For 766 patients with available tumor tissue, the presence of EBV in cancer cells was evaluated by EBV-encoded RNA in situ hybridization and correlated with clinical characteristics and treatment outcomes. Among the patients evaluated (n = 766), 40 (5.0%) were EBV-positive. EBVaGC was associated with male sex (p = 0.009) and lower neutrophil-lymphocyte ratio (NLR < 2.46, p = 0.03). Efficacy of first-line FP chemotherapy, in terms of response rate ad progression-free survival (PFS), did not differ between EBVaGC and EBV-negative GC (overall response rate: 53.8% vs. 51.8%, p = 0.99; median PFS: 6.4 vs. 6.7months, p = 0.90). However, overall survival tended to be better with EBVaGC than EBV-negative GC (16.4 vs. 14.0months, p = 0.07). EBVaGC accounted for 5% of metastatic/unresectable GCs. While EBVaGC was not associated with better response to or PFS following first-line cytotoxic chemotherapy, it showed a trend toward better overall survival.

Real-world response endpoints in patients with mNSCLC treated with chemotherapy across real-world datasets.

6595 Background: Response Evaluation Criteria in Solid Tumors (RECIST) based response rate (RR) is used for efficacy evaluation in clinical trials and relies on imaging data collected at specified timepoints for uniform assessment. In routine clinical practice, the method and timing of response assessment can vary, and imaging data from electronic health records (EHR) and other real world (rw) sources may not be available, making RECIST-based assessment of rw-response rate (rwRR) using rw data (RWD) challenging. Friends of Cancer Research formed a multi-stakeholder partnership to assess available data attributes to measure response across RWD sources to inform development of a consistent method for measurement. Methods: The study included seven EHR data partners who identified and analyzed a cohort of 1,380 patients (pts) with metastatic non-small cell lung cancer (mNSCLC) treated with first-line platinum doublet chemotherapy, following a common protocol and statistical analysis plan. The availability and frequency of data components to assess response including raw images, radiology imaging reports, and clinician response assessments from provider notes were assessed. Response endpoints measured included rwRR, rw-duration of response (rwDOR), and the association of rwR with rw-overall survival (rwOS), rw-time to treatment discontinuation (rwTTD), and rw-time to next treatment (rwTTNT). Results: The availability of data components varied across RWD sources (Table). Images were not widely accessible, thus response was analyzed using clinician response assessments (median proportion of pts evaluable, 77.5%). Of these assessments, the majority relied on imaging interpretation. The median rwRR was 46% with a median rwDOR of 119 days. The table provides median rwTTD, rwTTNT, and rwOS across data sources. Conclusions: The rwRR among pts with mNSCLC calculated using the clinician assessment was relatively consistent across all RWD sources, with consistent trends in time to event endpoints. While variability in the availability of data components to assess response was observed, the demonstrated feasibility of response endpoints based on clinician assessment suggests further exploration may inform drug effectiveness evaluation with RWD. [Table: see text]

Safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination in stage IV non-small-cell lung cancer: An open-label phase II trial (VinMetAtezo)

ObjectiveTo evaluate the safety and efficacy of second-line metronomic oral vinorelbine–atezolizumab combination for stage IV non-small-cell lung cancer. MethodsThis was a multicenter, open-label, single-arm Phase II study performed in patients with advanced NSCLC without activating EGFR mutation or ALK rearrangement who progressed after first-line platinum-doublet chemotherapy. Combination treatment was atezolizumab (1200 mg IV day 1, every 3 weeks) and oral vinorelbine (40 mg, 3 times by week). The primary outcome was progression-free survival (PFS) during the 4-month follow-up from the first dose of treatment. Statistical analysis was based on the exact single-stage Phase II design defined by A’Hern. Based on literature data, the Phase III trial threshold was set at 36 successes in 71 patients. Results71 patients were analyzed (median age, 64 years; male, 66.2%; ex-smokers/active smokers, 85.9%; ECOG performance status 0–1, 90.2%; non-squamous NSCLC, 83.1%; PD-L1 ≥ 50%, 4.4%). After a median follow-up of 8.1 months from treatment initiation, 4-month PFS rate was 32% (95% CI, 22–44), i.e. 23 successes out 71 patients. OS rate was 73.2% at 4 months and 24.3% at 24 months. Median PFS and OS were 2.2 (95% CI, 1.5–3.0) months and 7.9 (95% CI, 4.8–11.4) months, respectively. Overall response rate and disease control rate at 4 months were 11% (95% CI, 5–21) and 32% (95% CI, 22–44), respectively. No safety signal was evidenced. ConclusionMetronomic oral vinorelbine-atezolizumab in the second-line setting did not achieve the predefined PFS threshold. No new safety signal was reported for vinorelbine-atezolizumab combination.

Influence of first-line chemotherapy regimen on survival outcomes of patients with advanced urothelial carcinoma who received second-line immune checkpoint inhibitors.

The therapeutic landscape for advanced urothelial carcinoma (mUC) has changed significantly since studies establishing superiority of cisplatin as first-line therapy were conducted. Most patients who are eligible now receive either maintenance or second-line immune checkpoint inhibitors (ICI) and data comparing first-line platinum chemotherapy agents in this setting is limited. The objective of this study was to determine the impact of first-line platinum chemotherapy agent on survival for patients who receive second-line ICI. This is a retrospective cohort study of real-world data, performed from January 1, 2015, to March 21, 2021, included patients with a diagnosis of metastatic or locally advanced urothelial carcinoma. Exposure of interest was first-line platinum-doublet chemotherapy (gemcitabine and/or cisplatin or gemcitabine and/or carboplatin) followed by single-agent second-line ICI. The primary endpoint was overall survival from start of second-line therapy. 2,042 patients received either gemcitabine and cisplatin (gem/cis) or gemcitabine and carboplatin (gem/carbo) as first-line therapy. The primary analysis of 890 patients who received second-line single-agent ICI had a median follow-up was 24.2 months from initiation of second-line therapy. Important differences in baseline demographics and/or clinical factors between groups were age, performance status, incidence of upper tract disease, and cisplatin eligibility. Unadjusted overall survival (OS) calculated from start of second-line therapy was longer in patients who received gem/cis compared to gem/carbo followed by ICI (median 9.3 vs. 8.8 months, P = 0.0009). However, OS adjusted for covariates was not significantly different with a hazard ratio (HR) of 0.94 (95% CI, 0.79-1.13; P = 0.50). A separate time-varying covariate model also showed no association between OS and first-line gem/cis (HR 1.00 [95% CI, 0.84-1.19]) while receiving second-line ICI. Survival time on ICI in the second-line setting is the same regardless of choice of prior platinum agent (cisplatin vs. carboplatin) suggesting against specific synergy for one of these agents with ICI. However, a significantly greater proportion of patients in a landmark analysis had long-term benefit with cisplatin strongly supporting it is as the preferred first-line platinum agent.

Predictive significance of inflammatory indexes in metastatic nonsmall cell lung cancer patients treated with platinum-doublet chemotherapy.

Lung cancer is the leading cause of cancer-related deaths, worldwide. Despite immune checkpoint inhibitors and targeted therapy have revolutionized the treatment of metastatic nonsmall cell lung cancer (NSCLC), a significant proportion of patients are still treated with platinum-based chemotherapy. It is widely noticed that systemic inflammation plays an important role in the development and progression of many solid tumors. In this study, we aimed to analyze the predictive role of the systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and prognostic nutritional index (PNI) in patients with advanced NSCLC treated with first-line platinum-doublet chemotherapy. We retrospectively collected data of patients treated with first-line therapy for metastatic NSCLC. All patients were treated with first-line platinum-doublet chemotherapy. The patients were grouped based on the median values of SII, PNI, and NLR. The Mann-Whitney U test was used for comparisons between groups. The chemotherapy response rate (RR) was 75% in all patients. RR is statistically significantly lower in high SII, low PNI, and high NLR groups. High inflammatory indexes in metastatic NSCLC patients who were treated with platinum-doublet chemotherapy are related to low chemotherapy RR.

Adoption of consolidative durvalumab among patients with locally advanced non-small cell lung cancer.

e20550 Background: Soon after the publication of the PACIFIC trial, the Food and Drug Administration (FDA) approved durvalumab following definitive chemoradiation in patients with unresectable stage III non-small cell lung cancer (NSCLC). However, patterns of durvalumab adoption within the United States are currently unknown. We investigated the pace of uptake of durvalumab as well as patient and tumor characteristics associated with receipt of durvalumab following FDA approval. Methods: This study used the nationwide Flatiron Health database, a longitudinal electronic health record-derived de-identified database. During the study period, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). From this de-identified database, we selected patients with stage IIIB-C NSCLC who completed at least two cycles of first-line (1L) platinum doublet chemotherapy between February 16, 2018 (FDA approval date for durvalumab) and August 16, 2019, and did not develop disease progression over a follow-up period of at least 120 days after 1L chemotherapy. In the absence of radiation therapy and surgery details in the database, these criteria served as a proxy for selecting patients who were most likely to be eligible for consolidative durvalumab. We evaluated temporal trends in the uptake of durvalumab after completion of 1L chemotherapy using the Cochran-Armitage test, clustering the time periods in 3-month intervals. We also characterized patient and tumor characteristics associated with durvalumab receipt using the chi-square test and multivariable logistic regression. Results: A total of 424 patients were included in our study sample, among whom 282 (66.5%) patients had documentation of having received durvalumab after 1L chemotherapy. Within the first 3 months after FDA approval, 60.4% of potentially eligible patients received durvalumab, while in the final 3 months of the study period, this proportion rose modestly to 68.3% (p = 0.19). On univariable and multivariable analysis, patient characteristics like age, sex, race, insurance, smoking status, performance status, and comorbidity score, as well as tumor characteristics like histology, EGFR status, and PD-L1 status, were not significantly associated with receipt of durvalumab. However, there was significant geographic variability in receipt of durvalumab, ranging from 65.7% in the South to 85.3% in the Midwest (chi-square p = 0.04). Conclusions: Early adoption of durvalumab upon completion of 1L chemotherapy for stage IIIB-C lung cancer was rapid across the United States, starting at over 60% in the first three months after FDA approval. Regional variation appears to be a more powerful driver than patient characteristics in discrepancies of durvalumab dissemination. Further exploration into these regional variations may help improve guideline-concordant care.

Clinicopathologic, genomic, and tumor microenvironment correlates of aneuploidy and immunotherapy outcomes in NSCLC.

9119 Background: Cancer aneuploidy, an unbalanced number of chromosomes, is associated with somatic mutation rate, expression of proliferative genes, and altered immune signaling. Whether aneuploidy correlates to a distinct immunophenotype or impacts clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC is unclear. Methods: In NSCLCs which underwent targeted next-generation sequencing, we retrospectively analyzed the aneuploidy score (AS), defined as the sum of the number of altered chromosome arms. An unbiased recursive partitioning (URP) algorithm was used to investigate an AS cutoff to discriminate responders from non-responders to ICIs. Multiplexed immunofluorescence to quantify CD8+, Foxp3+, PD-1+, and PD-L1 expression was performed to determine differences in tumor immune cells subsets according to AS cutoff. Results: Among 436 NSCLCs identified, stage I tumors (median AS 1) had significantly lower median AS (mAS) than stage IV cancers (mAS 7, P &lt; 0.001), stage III (mAS 4, P = 0.03), and numerically lower compared to stage II cancers (mAS 3, P = 0.18). We found no difference in the mAS across tumors with a PD-L1 tumor proportion score of ≥50%, 1-49%, or &lt; 1% (mAS 5 vs 7 vs 6, respectively, P = 0.26), nor was there any correlation between aneuploidy and TMB when taken as continuous variables (Spearman R: 0.074, P = 0.12). A total of 279 advanced NSCLCs with available aneuploidy scores were treated with ICIs. An URP analysis identified an AS of 2 as the strongest discriminator of objective response to ICI. Compared to pts with an AS &gt; 2 (N = 207, 74.2%), pts with AS ≤2 (N = 72, 25.8%) had a significantly higher objective response rate (ORR 43.0% vs 19.8%, P &lt; 0.001), a significantly longer median progression-free survival (mPFS 6.2 vs 2.9 months, HR: 0.70 [95% CI: 0.52-0.94], P = 0.02), and a significantly longer median overall survival (mOS 19.8 vs 13.8 months, HR: 0.66 [95% CI: 0.47-0.94], P = 0.02) to treatment with ICIs. After adjusting for other variables such as performance status, presence of oncogenic driver mutation, PD-L1, TMB, and line of treatment, AS was significantly associated with improved mPFS (HR: 0.72 [95% CI: 0.52-0.99], P = 0.04) and mOS (HR: 0.64 [95% CI: 0.44-0.94], P = 0.02). By contrast, among pts who received first-line platinum doublet chemotherapy without ICI, an AS ≤2 (N = 29), when compared to an AS &gt; 2 (N = 56), did not correlate with improved ORR (55.2% vs 44.6%, P = 0.4) or PFS (5.3 vs 4.8 months, HR 0.83 [95% CI: 0.5-1.3], P = 0.43). Among 179 NSCLCs profiled by multiplex immunofluorescence, compared to cancers with an AS &gt; 2, those with low aneuploidy had significantly higher numbers of CD8+, Foxp3+, PD-1+ immune cells, and PD-1+ CD8+ T cell, both intratumorally and when looking at the total numbers of cells within the tumor and at the tumor-stroma interface. Conclusions: NSCLCs with low aneuploidy have a distinct immune microenvironment and more favorable outcomes to ICIs.

Metabolites as Prognostic Markers for Metastatic Non-Small Cell Lung Cancer (NSCLC) Patients Treated with First-Line Platinum-Doublet Chemotherapy.

The metabolic requirements of metastatic non-small cell lung (mNSCLC) tumors from patients receiving first-line platinum-doublet chemotherapy are hypothesized to imprint a blood signature suitable for survival prediction. Pre-treatment samples prospectively collected at baseline from a randomized phase III trial were assayed using nuclear magnetic resonance (NMR) spectroscopy (n = 341) and ultra-high performance liquid chromatography – mass spectrometry (UPLC-MS) (n = 297). Distributions of time to event outcomes were estimated by Kaplan-Meier analysis, and baseline characteristics adjusted Cox regression modeling was used to correlate markers’ levels to time to event outcomes. Sixteen polar metabolites were significantly correlated with overall survival (OS) by univariate analysis (p < 0.025). Formate, 2-hydroxybutyrate, glycine and myo-inositol were selected for a multivariate model. The median OS was 6.6 months in the high-risk group compared to 11.4 months in the low risk group HR (Hazard Ratio) = 1.99, 95% C.I. (Confidence Interval) 1.45–2.68; p < 0.0001). Modeling of lipids by class (sphingolipids, acylcarnitines and lysophosphatidylcholines) revealed a median OS = 5.7 months vs. 11. 9 months for the high vs. low risk group. (HR: 2.23, 95% C.I. 1.55–3.20; p < 0.0001). These results demonstrate that metabolic profiles from pre-treatment samples may be useful to stratify clinical outcomes for mNSCLC patients receiving chemotherapy. Genomic and longitudinal measurements pre- and post-treatment may yield addition information to personalize treatment decisions further.

Cost-effectiveness analysis of pembrolizumab monotherapy versus chemotherapy for previously untreated advanced non-small cell lung cancer

Objective: To assess the cost-effectiveness of pembrolizumab monotherapy compared with standard chemotherapy for the treatment of advanced non-small cell lung cancer (NSCLC) in previously untreated adults who have a high programmed death ligand 1 (PD-L1) tumor proportion score of 50% or greater in Singapore.Materials and methods: A partitioned-survival analysis model was developed from a healthcare system’s perspective that extrapolated clinical and economic outcomes of first-line pembrolizumab (maximum treatment duration of 2 years) versus platinum doublet chemotherapy over a 10-year time horizon for patients with advanced NSCLC. The model consisted of three health states: alive with no progression, alive with progression, and dead. Key clinical inputs were based on Kaplan-Meier survival curves from the interim (median follow-up = 11.2 months) and updated analysis (median follow-up = 25.2 months) of the KEYNOTE-024 randomized controlled trial. Local cost data were applied. Utilities were derived from published international estimates. Both one-way and multivariate probabilistic sensitivity analyses (PSA) were conducted to identify key drivers of the results.Results: Using the results from the updated analysis of KEYNOTE-024, patients treated with pembrolizumab experienced more quality adjusted life-years (QALYs), but incurred higher costs compared to chemotherapy over a 10-year time horizon (pembrolizumab: 1.9983 QALYs, SGD215,761; chemotherapy: 1.1317 QALYs, SGD70,444). The base-case incremental cost-effectiveness ratio (ICER) was SGD167,692 per QALY gained. One-way sensitivity analysis showed the ICER was most sensitive to the cost of pembrolizumab, followed by the time horizon. Multivariate PSA indicated that pembrolizumab had 0% probability of being cost-effective at a hypothetical willingness-to-pay threshold of SGD100,000 per QALY gained.Conclusion: While pembrolizumab is superior to standard chemotherapy in improving overall survival and progression-free survival, results suggest that it is unlikely to be cost-effective at its current price in Singapore. Factors including clinical effectiveness, safety, and budget impact should also be considered when making national funding decisions.

Prognostic role of mismatch repair deficiency (MMR-D) in patients receiving first-line fluoropyrimidine and platinum (FP) doublet chemotherapy for metastatic and locally advanced unresectable gastric cancers (GCs).

4566 Background: Although chemotherapy has been suggested to have the potential to cause a detrimental effect on treatment outcomes of localized GC with MMR-D, it remains unclear whether chemotherapy for metastatic/recurrent/unresectable GC with MMR-D would also adversely affect the survival outcomes. Anti PD-1 antibody (Ab) showed remarkable efficacy in patients with MMR-D and is being actively investigated in combination with cytotoxic chemotherapy. Hence, we aim to evaluate the impact of MMR status on treatment outcomes of advanced GC. Methods: We reviewed our database to identify all patients with HER2 negative, metastatic, recurrent, and locally advanced unresectable GC who received FP doublet chemotherapy from January 2015 to August 2018. For those who had an available tumor tissue, MMR protein expression was assessed by immunohistochemistry (IHC) and correlated with clinical characteristics and treatment outcomes. Results: Out of 895 patients identified from the database, 543 underwent IHC testing for MMR. The median age was 58 years (range, 24 – 86) with male comprising 64.0%. Most patients had initially metastatic disease (n = 382, 70.3%) followed by recurrent (n = 127, 23.3%) and locally advanced unresectable disease (n = 34, 6.3%). MMR-D was found in 4.4% (n = 24) and associated with age ≥ 65 years (50% vs. 29.9%; P = 0.04) and signet ring cell histology (0% vs. 17.7%, P = 0.01). According to our prognostic model (Koo DH et al, 2011), only 4.2% of patients with MMR-D were classified as Poor-risk group (vs. 16.8% of patients with MMR-P, p= 0.10). In the Good-risk group, patients with MMR-D (n = 10) had significantly shorter median progression-free survival (PFS, 6.0 vs. 9.0 months, P = 0.05) and overall survival (OS, 10.1 vs 20.9 months, P = 0.047) compared to those with MMR-P (n = 188), while there was no significant difference in survival outcomes depending on MMR status in the Moderate and Poor-risk groups. In multivariate analysis for OS, MMR status was a significant prognostic factor for OS in Good-risk group GC patients. Conclusions: GC patients with MMR-D had poorer median PFS and OS than those with MMR-P on standard cytotoxic chemotherapy in the Good-risk group. Thus, for Good-risk GC patients with MMR-D, anti PD-1 Ab alone might be considered rather than combining cytotoxic chemotherapy. Further investigation with next-generation sequencing is in process to determine underlying molecular mechanisms and will be presented in ASCO 2020.

Predictive role of mismatch repair deficiency (MMR-D) in patients receiving first-line fluoropyrimidine and platinum (F-P) doublet chemotherapy for metastatic and locally advanced unresectable gastric cancers (GC).

444 Background: Although adjuvant chemotherapy has been known to have a detrimental effect on MMR-D patients (pts) with resectable GC, it is unclear whether palliative chemotherapy for advanced GC would also adversely affect the survival outcome of MMR-D pts. Immune-checkpoint inhibitor (ICI) monotherapy was approved as a standard treatment for ≥ 3rd line of advanced GC and also showed a remarkable efficacy in MMR-D pts regardless of line of therapy. ICI is now being investigated in combination with 1st-line cytotoxic chemotherapy. Hence, we aim to evaluate the prognostic impact of MMR on cytotoxic chemotherapy in advanced GC. Methods: We reviewed our prospective database to identify pts with initally metastatic, recurrent and locally advanced unresectable GC who received F-P doublet from 2015 to 2018. MMR was assessed by immunohistochemistry with previously-collected tumor tissue and correlated with clinical characteristics and survival outcomes. Results: Out of 892 pts identified from the database, 543 underwent MMR test [382 initally metastatic (70.3%); 127 recurrent (23.3%); 32 locally advanced unresectable (6.3%)]. Median age was 58 years (range, 24–86) with male comprising 64.0%. MMR-D was found in 4.4% (n = 24) and associated with age ≥ 65 (50% vs 29.9%; P = 0.037), antrum-origin (62.5% vs 34.1%, P = 0.004) and well/moderately-differentiated histology (41.7% vs 25.8%, P = 0.110). According to our prognostic model (Koo DH et al, 2011), MMR-D pts were less likely to be classified into poor-risk group (4.2% vs 16.8%, P = 0.102). In good-risk group, MMR-D pts had significantly shorter PFS (6.0 vs 9.0 months, P = 0.045) and OS (10.1 vs 20.9 months, P = 0.047), while pts in moderate and poor risk group showed no difference in survival depending on MMR status. Conclusions: MMR-D GC showed significantly shorter PFS and OS on F-P doublet in good-risk pts and further investigation is needed to determine underlying molecular mechanisms. With the negative impact of MMR-D on the effect of cytotoxic chemotherapy, exclusion of MMR-D pts should be considered in future trials of ICI and cytotoxic chemothrapy combination.

Clinicopathologic Characteristics of BRG1-Deficient NSCLC.

Ten percent of NSCLCs harbor mutations in SMARCA4, the gene encoding the SWItch/Sucrose Non-Fermentable ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, CDK4, or CDK6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations. Data sets from Massachusetts General Hospital and Foundation Medicine were reviewed to determine the prevalence of SMARCA4-mutant NSCLC and describe its clinicopathologic characteristics. BRG1 expression was evaluated by immunohistochemistry and correlated with SMARCA4 mutations. Treatment outcomes were retrospectively assessed. We detected SMARCA4 genomic alterations in 9% (n= 117 of 1422) and 11% (n= 3188 of 27,281) of NSCLCs in the institutional and Foundation Medicine data sets, respectively. In both cohorts, truncating mutations comprised over one-third of SMARCA4 alterations. Twenty-nine of 64 SMARCA4-mutant NSCLCs (45%) assessed for BRG1 expression reported loss of expression, most (90%) of which had truncating SMARCA4 mutations. Overall, 84% (n= 26 of 31) of evaluated NSCLCs with truncating SMARCA4 mutations lacked BRG1 expression. Deficient BRG1 expression was predominantly detected in adenocarcinomas with co-occurring mutations in KRAS, TP53, KEAP1, and STK11. Among patients with BRG1-deficient NSCLC who received first-line platinum doublet chemotherapy (n= 11) or chemotherapy plus immunotherapy (n= 5), median progression-free survival was 38 days and 35 days, respectively. BRG1 deficiency is enriched in NSCLCs with truncating SMARCA4 mutations. Clinical outcomes are poor in this molecular subgroup, highlighting the importance of developing novel strategies to target unique vulnerabilities associated with the BRG1-deficient state.

Role of KEAP1/NFE2L2 Mutations in the Chemotherapeutic Response of Patients with Non-Small Cell Lung Cancer.

Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations that activate NFE2L2, including mutations in NFE2L2, KEAP1, or CUL3, have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored. We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 patients with stage IV NSCLC with KEAP1, NFE2L2, or CUL3 mutations and a matched cohort of 52 wild-type patients. Time to treatment failure after first-line platinum doublet chemotherapy and overall survival was compared between the two groups. Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In patients with NSCLC, median time to treatment failure (TTF) after first-line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared with 8.3 months in the control group (P < 0.0001). Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (P = 0.006). Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter TTF and OS after first-line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of patients with NSCLC are therefore needed.

P1.04-70 Application of Tumor Kinetics for Evaluation of Hyperprogression in Immune Checkpoint Inhibitor Treatment for Non-Small Cell Lung Cancer

Immune checkpoint inhibitors (ICIs) have suggested substantial options for treatment in advanced non-small cell lung cancer (NSCLC) without driver oncogenes. However, existing criteria for response assessment have limitations in differentiating categories of disease progression upon ICI treatment: primary resistance, pseudoprogression or hyperprogression (HPD). This study was aimed to investigate a real-world feasibility of pre- and on-treatment tumor kinetics for ICIs-specific response assessment in NSCLC. We retrospectively recruited stage III/IV NSCLC patients treated with anti-PD-1/PD-L1 monotherapy after failure of first-line platinum-doublet chemotherapy (n=91) between June 2016 and October 2018. Based on medical records from response-evaluable patients, we analyzed tumor kinetics prior and upon ICI treatment using ratio of tumor growth rate (TGR ratio, TGRR), tumor growth kinetics (TGK ratio, TGKR) and difference in TGR (delta TGR, ΔTGR), respectively. HPD was defined as TGRR≥2, TGKR≥2 and ΔTGR >50%. After excluding 18 patients without CT scan after start of ICIs, 73 patients were enrolled. Of response-evaluable patients, 47 patients (64%) stopped ICI treatment due to disease progression or death. Overall response rate by RECIST v1.1 was 16.4% (12/73) and disease control rate was 62% (45/73). HPD patients was 12% (9/73) and 15% (11/73) when defined by TGRR and TGKR, respectively. There was no HPD patients defined by ΔTGR. HPD patients classified by each criterion were associated with shorter median progression-free survival (PFS) according to iRECIST (TGRR ≥2, 1.6 vs 2.1 months, p<0.001; TGKR ≥2, 1.6 vs 2.1 months, p<0.001) and median overall survival (OS) than non-HPD-PD patients (TGRR ≥2, 2.4 vs 5.2 months, p=0.002; TGKR ≥2, 2.4 vs 5.2 months, p=0.002). HPD was not associated with age, sex, histology, stage, brain metastasis, nor PD-L1 expression at baseline. There was no pseudoprogression in patients classified as HPD. HPD defined by pre- and on-treatment tumor kinetics was observed in 12-15% of patients with advanced NSCLC treated with second-line ICI monotherapy, and correlated with shorter PFS and OS. TGR and TGK could classify HPD patients from non-HPD PD with similar discriminability. Further studies are needed to investigate clinical and molecular determinants that distinguish HPD from non-HPD PD and pseuoprogression.

Abstract CT158: ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer

Abstract Background: The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib has demonstrated clinical activity in patients with ovarian cancer with or without homologous recombination (HR) deficiency (HRD; eg, a BRCA mutation or high genome-wide loss of heterozygosity [LOH high]). ATHENA (NCT03522246) is evaluating rucaparib + the anti-PD-1 antibody nivolumab as maintenance treatment following front-line platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for evaluating this combination includes the following: tumors with a deleterious BRCAmutation express novel, tumor-specific protein sequences (neoantigens), which can attract PD-L1-expressing, tumor-infiltrating lymphocytes; ovarian tumors with HRD have more neoantigens relative to HR-proficient tumors and may respond preferentially to immune checkpoint inhibitors; and rucaparib combined with anti-PD-1 or anti-PD-L1 demonstrated improved antitumor activity in a syngeneic ovarian cancer BrKras (BRCA1-/-; TP53-/-; MYC; KRAS-G12D; AKT) model. Furthermore, it is hypothesized that DNA damage induced by PARP inhibition may increase neoantigens regardless of HRD status. Methods: Eligible patients must have completed first-line platinum doublet chemotherapy and surgery. Patients had to have achieved an investigator-assessed response without disease progression or rising CA-125 at any time during first-line platinum doublet treatment. Cytoreductive surgery (R0 permitted) could have been completed either prior to chemotherapy (primary surgery) or following neoadjuvant chemotherapy (interval debulking). Patients will be randomized 4:4:1:1 to receive maintenance treatment in Arm A (oral rucaparib 600 mg BID + intravenous [IV] nivolumab 480 mg on day 1 of every 4-week cycle), Arm B (oral rucaparib + IV placebo), Arm C (oral placebo + IV nivolumab), or Arm D (oral placebo + IV placebo). Stratification factors include centrally determined tumor HRD status (BRCA mutant, non-BRCA mutant/LOH high, non-BRCA mutant/LOH low, or non-BRCA mutant/LOH indeterminate), posttreatment disease status (residual vs no residual disease), and timing of surgery (primary vs interval debulking). The primary endpoint of investigator-assessed progression-free survival (per RECIST version 1.1) will be evaluated in 3 independent comparisons between arms: A vs B, A vs D, and B vs D. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, investigator-assessed objective response rate, investigator-assessed duration of response, and safety. Enrollment is ongoing; patients (n≈1000) will be enrolled at &amp;gt;270 sites worldwide. Citation Format: Shannon N. Westin, Rebecca S. Kristeleit, Robert L. Coleman, Keiichi Fujiwara, Amit M. Oza, David M. O’Malley, Thomas J. Herzog, Frederik Marmé, Ana Oaknin, Ramez Eskander, Domenica Lorusso, Tamar Safra, Jacob Korach, Kevin K. Lin, Danny Shih, Lisa Caunt, Sandra Goble, Stephanie Hume, Lara Maloney, Iain McNeish, Bradley J. Monk. ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT158.

Abstract 748: Genomic characterization of recurrent small cell lung cancer through research autopsy reveals clonal diversity and candidate driver of chemoresistance

Abstract Genomic characterization of recurrent small cell lung cancer (SCLC) is needed to dissect the molecular mechanisms of relapse, metastatic dissemination, and chemoresistance. SCLC is a highly aggressive, lethal neuroendocrine cancer arising from the bronchial epithelium that develops in heavy smokers. Although many SCLC patients demonstrate sensitivity to first-line platinum-doublet chemotherapy, the response is short-lived and nearly all patients progress during therapy or relapse within several months of completing treatment. Treatment options beyond first-line chemotherapy are limited and ineffective. Metastatic SCLC has a poor prognosis and is associated with a 5-year overall survival rate of 5-10%. A well-characterized genetic hallmark of SCLC is the concurrent inactivation of tumor suppressor genes TP53 and RB1. Additional SCLC candidate driver genes have been reported and include CREBBP, MLL, NOTCH1-4, SOX2 and MYC. However, most SCLC tumors profiled in these studies were obtained from treatment-naïve patients. Therefore, genomic alterations that are acquired during therapy and drive the development of chemoresistance in recurrent SCLC remain undefined. We present results from whole exome sequencing (WES) of multiple metastatic tumors procured from five treatment-refractory SCLC patients who underwent research autopsy. WES was also performed on pre-treatment samples from three of these patients. Our results showed universal TP53 alterations and to a lesser extent RB1 mutations in our SCLC cohort. Next, we utilized bioinformatics methods to analyze clonal heterogeneity and evolution in these SCLC patients. This analysis demonstrated the existence of multiple clones of tumor cells in both the pre-treatment and treatment-resistant autopsy SCLC samples, suggesting that tumor heterogeneity occurs early in SCLC development and is subsequently maintained. Furthermore, allele-specific analysis of copy number variations in our SCLC cohort demonstrated near universal deletion of a region on chromosome 5q containing the tumor suppressor APC, consistent with a recently reported role for deregulated WNT signaling in chemoresistance development in relapsed SCLC. Finally, in one SCLC patient, we identified PTEN deletion (loss of heterozygosity) as a potential mechanism of metastasis specifically to the brain. In conclusion, we have performed genomic characterization of recurrent SCLC, defined by significant clonal diversity, through research autopsy and identified candidate genetic drivers of treatment resistance and organ-specific metastasis. Citation Format: Hui-Zi Chen, Russell Bonneville, Melanie A. Krook, Michele R. Wing, Julie W. Reeser, Jharna Miya, Anoosha Paruchuri, Eric Samorodnitsky, Lianbo Yu, Amy M. Smith, Thuy Dao, Dorrelyn Martin, Qishan Guo, Hailey Magenheim, Aharon G. Freud, Sharon Cole, Gregory Otterson, Peter Shields, David P. Carbone, Patricia Allenby, Sameek Roychowdhury. Genomic characterization of recurrent small cell lung cancer through research autopsy reveals clonal diversity and candidate driver of chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 748.