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Mari Mino-Kenudson



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    FP01 - Early Stage/Localized Disease (ID 111)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP01.05 - The ASCENT Trial: A Phase II Study of Neoadjuvant/Adjuvant Afatinib, Chemoradiation +/- Surgery for Stage III EGFR-Mutant NSCLC (ID 3752)

      00:00 - 00:00  |  Author(s): Mari Mino-Kenudson

      • Abstract

      Introduction

      The ADAURA trial showed benefit to adjuvant osimertinib in stage III EGFR-mutant (EGFRm) NSCLC, but the role of TKI induction is unknown. In 2011, we began ASCENT, a phase II trial of neoadjuvant and adjuvant afatinib in addition to standard of care (SOC) curative-intent therapy for EGFRm stage III NSCLC (NCT01553942). The study closed early for slow accrual. This is the final analysis.

      Methods

      ASCENT enrolled patients with EGFRm, stage IIIA/B (AJCC 7th ed.) NSCLC amenable to curative-intent chemoradiation therapy (CRT) ± surgery. Resectability was determined by the treating multidisciplinary team at diagnosis. Patients received neoadjuvant afatinib 40mg QD x 2 months, then concurrent CRT (up to 4 cycles of cisplatin/pemetrexed and 3D conformal RT or intensity-modulated RT personalized to tumor size, site, operability) +/- surgery and an optional 2 years of adjuvant afatinib. The primary outcome was objective response rate (ORR) to neoadjuvant afatinib. Major pathologic response (MPR) was defined as < 10% residual tumor at resection, complete pathologic response (CPR) as no residual tumor.

      Results

      19 patients (14F/5M), median age 56 (range 34-75) were enrolled. 12 had EGFR del19, 7 L858R. 10 were classified as potentially resectable stage IIIA at diagnosis, 9 as unresectable IIIA/B. All completed two months of neoadjuvant afatinib; 5 (26%) required afatinib dose reduction. The ORR after neoadjuvant afatinib was 11/19 (58%; 95% CI, 33-80%). 1 patient initially deemed inoperable became a surgical candidate based on response to neoadjuvant afatinib; 2 patients progressed on neoadjuvant afatinib or exhibited findings that clarified their presenting stage as IV; both discontinued the protocol. The remaining 17 patients proceeded to CRT with pre-op median radiotherapy dose of 54 Gy (range 45-66; n=10), definitive median dose of 67 Gy (range 63-72; n=7). Among 10 patients who underwent resection (all via lobectomy), the MPR rate was 70% (6 MPR, 1 CPR). 13 (68%) patients started adjuvant afatinib after surgery (7) or definitive CRT (6); 4 completed 2 years, 3 discontinued early (median 1.5 months), 2 recurred during adjuvant afatinib and 4 remain on adjuvant therapy. Key grade 3/4 toxicities included rash (n=6), diarrhea (5), esophagitis (3), nausea (3), pneumonitis (2) and febrile neutropenia (1); there were no treatment-related deaths. With median follow-up of 30.6 months (range 3.1-96.3), 9 (47%) patients have recurred, with 5/9 having CNS-only recurrence. Recurrences occurred in 3/10 surgical patients and 5/7 definitive CRT patients. Median PFS was 34.6 months (95% CI 16.9-66.1) and median OS was 69.1 months (95% CI 29.4-NR). 2-year OS is 88% (95% CI 59-97%).

      Conclusion

      In stage III EGFRm NSCLC, 2 months of neoadjuvant afatinib is associated with an ORR comparable to that seen in advanced disease and does not impair receipt of SOC chemoradiotherapy ± surgery. PFS and OS are favorable in this single-arm study. The high rate of CNS-only recurrence highlights a potential for improved outcomes with more CNS-penetrant EGFR TKIs. Along with the interim results of ADAURA, these results support genotype-directed therapies in stage III EGFRm NSCLC, though the optimal sequence of TKI therapy will need to be defined.

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    P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P14.03 - Increased Tumor-Associated LAG-3+ Lymphocytes Correlate with Aggressive Tumor Behavior and Worse Prognosis in Lung Adenocarcinoma (ID 1194)

      00:00 - 00:00  |  Author(s): Mari Mino-Kenudson

      • Abstract

      Introduction

      Immune checkpoint blockade targeting the PD-1/PD-L1 axis has become a mainstay of treatment for advanced non-small cell lung cancer. However, only a subset of patients benefits, with long-term efficacy limited by primary and secondary resistance. Resistance to PD-1 axis blockade is attributed in part to the upregulation by T-lymphocytes of regulatory molecules such as lymphocyte activation gene-3 (LAG-3). This study examined the role of LAG-3+ T-lymphocytes in the lung adenocarcinoma microenvironment through correlation with clinicopathologic features and patient outcomes.

      Methods

      Immunohistochemistry for LAG-3 and CD8 was performed on 225 lung adenocarcinomas resected in 2010-2012 using tissue microarrays (duplicate of 2-mm core). The number of LAG-3+ lymphocytes was quantified in 3 high-power fields (HPF; each 0.24 mm2) for each of the two duplicate samples, and CD8+ tumor-associated lymphocytes (both stromal and tumor-infiltrating) were also quantified. LAG-3+ lymphocytes, CD8+ T-cells, and the ratio of LAG-3+/CD8+ T-cells were correlated with clinicopathologic features, PD-L1 expression, and patient outcomes.

      Results

      In lung adenocarcinomas from 225 patients (141 women, 84 men; age 39-89 [median 69] years; 79% smokers; 88% stages 1-2; 40.4% KRAS-mutant; 21.3% EGFR-mutant), the number of LAG-3+ cellsranged from 0 to 540.1/mm2 (median 7.0/mm2), and the number of CD8+ tumor-associated lymphocytes ranged from 34.8 to 5205.3/mm2 (median 626.7/mm2). Higher numbers of LAG-3+ cells were associated with smoking history (p<0.001) and features of aggressive tumor behavior, including solid-predominant histologic pattern, presence of lymphovascular invasion, and presence of nodal metastasis (all p<0.01). Larger overall tumor size and invasive tumor size correlated with LAG-3+ cells when normalized to CD8+ cell counts (LAG-3/CD8 ratio; p<0.05). In terms of molecular features, KRAS-mutant tumors were associated with significantly higher numbers of LAG-3+ cells versus EGFR-mutant tumors (p<0.01). LAG-3+ cell count was positively correlated with both PD-L1 H score and CD8+ tumor-associated lymphocytes (all p<0.01). Lastly, patients with tumors harboring an increased LAG-3/CD8 ratio (i.e., above the median) showed significantly worse overall survival, irrespective of PD-L1 expression (p=0.027).

      Conclusion

      Increased LAG3+ T-lymphocytes were associated with smoking history, adverse histologic features, worse survival, and increased PD-L1 expression in lung adenocarcinomas. Given the known role of LAG-3 in dampening the immune response, high LAG-3 expression may be associated with decreased efficacy of PD-1 axis blockade. Additional studies to evaluate the predictive value of LAG-3 in patients with lung adenocarcinoma undergoing immune checkpoint blockade are warranted.

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    P38 - Pathology - Pathology/Staging (ID 108)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P38.02 - Reproducibility and Accuracy of Intra-Operative Assessment on Tumor Spread Through Air Spaces in Stage 1 Lung Adenocarcinomas (ID 1819)

      00:00 - 00:00  |  Author(s): Mari Mino-Kenudson

      • Abstract

      Introduction

      STAS has been associated with worse prognosis in patients with early-stage lung adenocarcinoma, particularly those undergoing sublobar resection. Intra-operative consultation (IC) of STAS has been advocated by some surgeons to guide surgical management. However, to date, information regarding the reproducibility and accuracy of frozen section (FS) for STAS diagnosis is limited. Thus, we assessed inter-observer (IOA) and intra-observer agreement among pathologists evaluating STAS in FS, and its diagnostic yield for detecting STAS. Preliminary data were previously presented at a conference and we now report the results of more detailed analyses with a larger study cohort.

      Methods

      We retrospectively evaluated 100 T1 lung adenocarcinoma resections assessed by IC and with ample non-neoplastic lung parenchyma in FS slides. A consensus panel of 3 pathologists jointly reviewed all histology slides, documented the diagnosis on STAS (+/-) and artifacts (+/-) per published criteria (Kadota, 2015), and recorded several histological parameters in each case. Five pulmonary pathologists blinded to clinicopathologic data, independently reviewed FS slides in each case on two separate rounds, and recorded the presence of STAS and artifacts per same criteria. The second round occurred after a consensus conference in which selected cases with low IOA were discussed. IOAs on STAS were assessed using the Fleiss-kappa statistics and were correlated with several pathologic features including the presence of artifacts. Diagnostic yield was determined by comparing consensus diagnoses made by >3 observers in the FS slide with the final diagnosis of the consensus panel, and assessed by receiver operating characteristic curves (ROC).

      Results

      There was a high variability in the prevalence of STAS in FS reported by all observers on both rounds (mean: 33% and 35.4%, respectively). The Fleiss-kappa value for the STAS diagnosis in FS slides among the 5 observers was 0.45 in the first round and only slightly increased in the second round (0.51), while the intra-observer agreement on STAS diagnosis in FS between both rounds were relatively high ranging from 67.9 to 82.5% (mean: 76.8%). The sensitivity (44%) for detecting STAS in FS was low, while the specificity (91%) was high. Overall, FS showed a 71% accuracy for STAS diagnosis, a positive likelihood ratio of 5.0, a negative likelihood ratio of 0.6, and a ROC/AUC of 0.67 (95%CI: 0.56-0.78). IOA for the FS diagnosis of STAS on both rounds was significantly higher in low-grade tumors (p<0.0001; Fig. 1A), in those with no STAS based on the entire tumor assessment (p<0.0001; Fig. 1B), in those with no artifacts identified by more than 3 observers (p<0.0001; Fig. 1C), and in those STAS-positive cases with five or more STAS-clusters identified in FS compared to less than 5 clusters (p=0.009; Fig. 1D).

      Conclusion

      FS is highly specific but not sensitive for the diagnosis of STAS in Stage I lung adenocarcinoma. IOA on STAS was moderate in FS, and improved only marginally after a consensus conference, raising concerns about the global implementation of IC in STAS assessment. Multi-Institutional studies aimed to standardize criteria for STAS and artifacts, and to improve intraoperative techniques are warranted.