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Jack A Roth
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MA19 - Genomic Markers of IO Response (ID 922)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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MA19.10 - Impact of STK11/LKB1 Genomic Alterations on Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (ID 14295)
16:15 - 16:20 | Author(s): Jack A Roth
- Abstract
- Presentation
Background
Chemo-immunotherapy with pemetrexed/carboplatin/pembrolizumab represents a standard of care for the first-line treatment of patients with metastatic non-squamous NSCLC, irrespective of tumor cell PD-L1 expression. Genomic determinants of response to chemo-immunotherapy in NSCLC have not been reported thus far. We previously identified STK11/LKB1 alterations as a major genomic driver of de novo resistance to PD-1/PD-L1 inhibitor monotherapy in NSCLC (Skoulidis et al., Cancer Discovery, 2018). Here, we examine the impact of STK11/LKB1 mutations on clinical outcomes with chemo-immunotherapy with pemetrexed/carboplatin/pembrolizumab.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with metastatic non-squamous NSCLC that received at least 1 cycle of pemetrexed/carboplatin/pembrolizumab at MD Anderson Cancer Center, were alive for ≥14 days thereafter and had available next generation sequencing- based comprehensive tumor genomic profiling were eligible. Response assessment was based on RECIST1.1. PD-L1 expression on tumor cells was evaluated using the FDA-approved 22C3 pharmDx assay. All patients consented to collection of clinical and molecular data as part of the GEMINI protocol.
4c3880bb027f159e801041b1021e88e8 Result
Among 49 eligible patients (median age 61 years, 51% female, 96% adenocarcinoma histology, 34.7% KRAS-mutant) the objective response rate to pemetrexed/carboplatin/pembrolizumab was 51% (25/49) for the overall population. The disease control rate (PR+SD≥ 6 months) differed significantly between STK11/LKB1-mutant and STK11/LKB1-wild-type tumors (31.3% vs 72.7%, P=0.011, two-tailed Fisher’s exact test). The objective response rate was 31.3% for STK11/LKB1-mutant and 60.6% for STK11/LKB1 wild-type tumors (P=0.07, two-tailed Fisher’s exact test). 37.5% (6/16) of STK11/LKB1-mutant tumors exhibited progressive disease as best overall response to chemo-immunotherapy compared with 6.1% (2/33) STK11/LKB1-wild-type tumors (P=0.01, two-tailed Fisher’s exact test). Patients bearing STK11/LKB1-mutant tumors exhibited shorter progression-free survival with chemo-immunotherapy (median PFS 4.4 months vs 11.0 months, P=0.039, log-rank test). STK11/LKB1-mutant tumors were less likely to be positive for PD-L1 expression (PD-L1 TPS ≥ 1%), although the difference did not reach statistical significance (43.8% vs 72%, P=0.1, two-tailed Fisher’s exact test).
8eea62084ca7e541d918e823422bd82e Conclusion
STK11/LKB1 genomic alterations are associated with inferior clinical outcomes with chemo-immunotherapy in non-squamous NSCLC, with response rates comparable to those previously reported for platinum doublet chemotherapy alone. Assessment of STK11/LKB1 status may help refine treatment approaches in non-squamous NSCLC.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MA23 - Early Stage Lung Cancer: Present and Future (ID 926)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 10:30 - 12:00, Room 105
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MA23.02 - Circulating Tumor DNA Analysis with a Novel Variant Classifier for Recurrence Detection in Resected, Early-Stage Lung Cancer (ID 13498)
10:35 - 10:40 | Author(s): Jack A Roth
- Abstract
- Presentation
Background
ctDNA is a blood-based biomarker with promising potential in lung cancer for minimal residual disease (MRD) assessment and early detection of recurrence. However, data regarding feasibility are limited, especially for stage I-II disease.
a9ded1e5ce5d75814730bb4caaf49419 Method
We performed longitudinal plasma ctDNA profiling of early-stage lung cancer patients (pts) that underwent resection at MD Anderson Cancer Center from Apr 2016 to Jan 2017. Plasma ctDNA was analyzed from pre-operative and multiple post-operative time points until disease recurrence. ctDNA profiling was performed using a 30kb Digital Sequencing panel (Guardant Health) covering SNVs in 21 genes and indels in 9 genes that are commonly present in lung cancer. ctDNA profiles from ~30,000 lung cancer pts were used to train a classifier to exclude non-tumor related mutations.
4c3880bb027f159e801041b1021e88e8 Result
A total of 40 pts were included in this analysis, comprised of the first 17 pts with recurrence in the longitudinal study and 23 consecutive pts without recurrence. This cohort was primarily stage I and II (15 [38%], 16 [40%]). Histology included adenocarcinoma (29 [73%]), SCC (6 [15%]), and SCLC (2 [5%]). 58% had adjuvant therapy. Median follow-up was 17.7 (3.4 – 24.5) months and median time to recurrence was 7.1 (3.4 – 16.5) months in this selected cohort. At least one ctDNA alteration was detected in 55% (21/38) of pts with evaluable pre-op samples and in 22% (8/37) of pts at 4 weeks post-op. Presence of ctDNA at 4 weeks post-op heralded eventual recurrence with 43% sensitivity and 91% specificity (75% PPV, 73% NPV) and was significantly associated with worse recurrence free survival (p=0.022, HR 6.52; 95% CI 1.3 – 32.6), while also accounting for stage. In the absence of the variant classifier, an additional 7/37 pts had non-tumor alterations detected at 4 weeks post-op with a recurrence sensitivity and specificity of 57.1% and 69.6%. ctDNA was identified in 76% (13/17) of pts prior to or at the time of recurrence. The median interval between ctDNA detection and radiographic recurrence was 91 days.
8eea62084ca7e541d918e823422bd82e Conclusion
Detection of post-op ctDNA, as early as 4 weeks after resection of early-stage lung cancer, is associated with significantly increased risk of recurrence. Accurate detection of ctDNA in this MRD setting is enabled by a highly sensitive sequencing platform that incorporates a novel variant classifier to enhance clinical specificity.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.03 - Biology (Not CME Accredited Session) (ID 935)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.03-12 - PD-L1 Expression is Predominant in CD68+ Tumor-Associated Macrophages in Stage I-III Non-Small Cell Lung Cancers (ID 13340)
16:45 - 18:00 | Author(s): Jack A Roth
- Abstract
Background
PD-L1 tumor expression is a leading biomarker in metastatic non-small lung cancer (NSCLC). Its role and expression in surgically resectable lung cancers is not yet defined. The association between PD-L1 expression on tumor and CD68+ tumor-associated macrophages (TAMs) and the inflammatory cells within the tumor microenvironment continues to be studied. We analyzed 97 surgically resected lung cancers utilizing immunofluorescence profiling and flow cytometry (n=47) with the aim of defining PD-L1 expression and its association with tumor inflammatory cells.
a9ded1e5ce5d75814730bb4caaf49419 Method
Multiplex immunofluorescence profiling of lung cancers was performed with the focus on malignant cells (MC), MC PD-L1%, CD3+, CD8+, PD-1+ cells, CD68+, CD68+ PD-L1%, and CD20+ cells. Data on cell populations were expressed as the number of cells per mm2, PD-L1 expression as percentage. Flow cytometry was performed on freshly disaggregated tumor samples. The associations of cell populations with clinical and pathologic characteristics were assessed using Spearman's rank correlation coefficient and Wilcoxon rank-sum test.
4c3880bb027f159e801041b1021e88e8 Result
97 patients, 55 (57%) female and 42 (43%) male, with median tumor size 4.0 cm underwent surgical resection for pathologic stage I (N=39), stage II (N=34), and stage III (N=24) NSCLC. 85 (88%) were former smokers, 12 (12%) never smokers. 62 (65%) had adenocarcinoma, 25 (25%) squamous cell carcinoma, 10 (10%) other histology. Neoadjuvant chemotherapy was administered in 16 (16%) patients. R0 resection was achieved in 89 (92%) patients. At the median follow-up duration of 16 months, 18 patients experienced recurrence.
CD68+ cells were less abundant than MC within tumor environment (median 120 cell/mm2 vs 4699, p<0.0001). However, PD-L1% expression was significantly higher on CD68+ vs MC within the tumor (median 33% vs 0.02%, p<0.0001); this was true for all stages. CD68+ PD-L1% in SCC was higher compared to adenocarcinoma (median 55% vs 30%, p=0.26). Induction chemotherapy increased CD68+ PD-L1% (median 31% no chemo vs 58%, p=0.05) without affecting the proportion of effector CD8+ TIL expressing its receptor, PD-1 (p=0.757). Tumors with > median CD68+ PD-L1% expression were associated with higher CD3+ (p=0.006), CD8+ (p=0.06), and CD68+ (p=0.004) cell numbers within the tumor.
8eea62084ca7e541d918e823422bd82e Conclusion
In early NSCLC PD-L1% expression appears to be predominant in CD68+ TAMs rather than in malignant cells. Higher than median PD-L1% expression on CD68+ is associated with increased in CD3+ and CD8+ T cells. Further studies are required to understand the role of CD68+PD-L1 cells within tumor microenvironment, the influence of neoadjuvant chemotherapy or immunotherapy regimens on these cells, and their effect on outcomes.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.09 - Pathology (Not CME Accredited Session) (ID 975)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.09-27 - Histopathologic Parameters Define Features of Treatment Response to Neoadjuvant Chemotherapy in Non-Small Cell Lung Cancer (ID 14257)
12:00 - 13:30 | Author(s): Jack A Roth
- Abstract
Background
Previous studies indicate that neoadjuvant chemotherapy improves survival in patients with loco-regionally advanced non-small cell lung cancer (NSCLC). The amount of residual viable tumor has been associated with long-term overall survival. This histopathologic measure has potential to become a standard method for evaluation of the effectiveness of neoadjuvant therapy regimens. However, adequate comparison of chemotherapy-treated and untreated lung cancers is lacking. We analyzed histopathologic characteristics of resected NSCLC with and without prior neoadjuvant chemotherapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Histopathologic assessment was performed of specimens obtained from patients enrolled on the immunogenomic lung cancer study (ICON), which integrates clinical, pathologic, immune, genomic and outcome data from surgically resected NSCLC. Cases included material from 10 patients who underwent neoadjuvant chemotherapy and 10 patients treated with primary surgery (adenocarcinoma, n=5; squamous cell carcinoma, n=5; for each cohort). Hematoxylin and eosin-stained tumor sections (mean, 6; range, 3-10) were evaluated and semiquantitatively scored for parameters commonly attributed to treatment response. The percentage of viable tumor was estimated by comparison to the proportion of fibrosis and necrosis on each slide. Additional parameters analyzed included the presence of inflammation, tertiary lymphoid structures (TLS), macrophages, lymphovascular invasion (LVI), cholesterol clefts, giant cells and neovascularization (score 0-3). For each patient, the results for all slides were averaged to determine a mean value. P values were calculated using the Mann-Whitney test.
4c3880bb027f159e801041b1021e88e8 Result
All histopathologic parameters typically associated with treatment response could also be identified in untreated specimens, albeit in different proportions. Compared to the untreated cohort, samples after chemotherapy were characterized by lower proportion of viable tumor (42.4% vs 67.7%, p=0.04) and higher degrees of fibrosis (46.6% vs 26.6%, p=0.08), and necrosis (11.0 % vs 5.6%, p=0.35). Among the additional parameters, similar scores were seen for inflammation (1.54 vs 1.46, p=0.60), TLS (1.00 vs 0.80, p=0.47), LVI (0.16 vs 0.23, p=0.62), and neovascularization (both 0) while macrophages (0.94 vs 0.12, p=0.20), cholesterol clefts (0.92 vs 0.13, p= 0.03) and giant cells (0.80 vs 0.40, p=0.17) were more common among the neoadjuvant cohort.
8eea62084ca7e541d918e823422bd82e Conclusion
Histopathologic variables commonly associated with chemotherapy treatment response can also be identified in treatment naïve lung cancers. However, the amount of viable tumor, fibrosis and cholesterol clefts are parameters strongly associated with neoadjuvant therapy. These results highlight the importance of assessing the type and extent of treatment response. Analysis of larger patient cohorts will reveal potential prognostic value in primary tumors, chemotherapy-treated, and eventually immunotherapy-treated tumors.
6f8b794f3246b0c1e1780bb4d4d5dc53
