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Mark G Kris



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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.09 - Neoadjuvant Atezolizumab in Resectable Non-Small Cell Lung Cancer (NSCLC): Updated Results from a Multicenter Study (LCMC3) (ID 12941)

      14:30 - 14:35  |  Author(s): Mark G Kris

      • Abstract
      • Presentation
      • Slides

      Background

      Cisplatin-based chemotherapy, before or after surgery, provides only a 5% benefit in 5yr. OS in resectable NSCLC. A 20 patient study (NEJM April 2018) showed that preoperative immune checkpoint inhibitor therapy yielded a clinically meaningful major pathologic response rate (MPR ≤10% residual viable tumor cells) and did not delay or complicate surgery. This large multicenter trial measures MPR and biomarkers of benefit using neoadjuvant atezolizumab (atezo) [NCT02927301].

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We planned 2 cycles of atezo (1200mg, days 1, 22) in patients with stages IB -selected IIIB resectable NSCLC prior to surgical resection (day 40 +/- 10). Chest CT, PET were planned pre-atezo and presurgery to assess response. Primary tumor +/- node biopsies and blood samples were obtained before atezo and presurgery for biomarker studies. The primary endpoint was MPR. Secondary endpoints included safety, response by PD-L1, OS, and DFS.

      4c3880bb027f159e801041b1021e88e8 Result

      For this updated efficacy and safety analysis (Feb’18 datacut), we report first 54 of 180 planned pts: 29 males, median age 65 yr, all ECOG 0-1; 17 current, 33 former smokers; 35 non-squamous NSCLC; clinical stages Ib/IIa/IIb/IIIa/IIIb = 5/11/13/20/5. Two pts received one dose of atezo due to treatment related AE (Gr 1 pyrexia, Gr 2 dyspnea) but underwent uncomplicated resection with MPR assessment. There was 1 unrelated Gr 5 AE (sudden cardiac death post surgical resection), 16 Gr 3-4 AEs (3 treatment related). Surgery was delayed in 1 pt due to Gr3 pneumonitis. By RECIST, 3 pts had PR, and 49 had SD. 50 pts underwent surgery and 47 pts had MPR assessment: 2 pts discontinued study preop due to radiographic PD and 2 discontinued due to other reasons; 3 pts had unresectable disease. MPR rate was 10/50 (20%, 95% CI 10-34%) including 3 pts who had pCR (no viable tumor cells) in the primary tumor. Excluding 5 pts who had known driver mutations (4 EGFR+, 1 ALK+), MPR rate was 10/45 (22%, 95% CI 11-37%). PD-L1 status was evaluable in 44/54 pts; 8/10 pts with MPR had PD-L1+ status and 2 had unknown PD-L1 status; 8/28 PDL-1 (+) patients had MPR (29%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a multicenter study, neoadjuvant atezo was well tolerated. MPR rate is encouraging. Clinical and pathological responses are often discordant. Correlative analyses on pre- and post atezo tissues are ongoing. Preliminary correlative analyses in blood samples are included in a separate abstract.

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      MA04.10 - Comprehensive Peripheral Blood Immunophenotyping and T-Cell Clonal Analysis During Neoadjuvant Immunotherapy with Atezolizumab in NSCLC (ID 13118)

      14:35 - 14:40  |  Author(s): Mark G Kris

      • Abstract
      • Presentation
      • Slides

      Background

      Immune-checkpoint blockade targeting PD-L1/PD-1 to activate anti-tumor immunity is associated with improved response rates and survival compared to chemotherapy in selected metastatic NSCLC patients. Evaluation of the pre-therapeutic immune profile and its treatment-related evolution associated with clinical benefit will guide future immunotherapy development and support clinical decision-making. Here, we present an analysis of peripheral blood (PB) immunophenotyping and T-cell-receptor (TCR) clonality before and after immunotherapy from an ongoing 180-patient phase II study of atezolizumab as neoadjuvant therapy with stage IB-IIIB resectable NSCLC (NCT02927301; LCMC3).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      As of February 5th datacut, the first 54 enrolled and dosed patients are presented. The biomarker evaluable population (BEP) further subset to patients with paired PB samples analyzed within 72 hours after collection and a major pathological response (MPR) assessment. Comprehensive immune cell phenotyping (10-color flow cytometry, IMMUNOME) and TCR-Vß-analysis by flow cytometry were performed. Immunoprofile analyses were correlated with atezolizumab treatment, pathological response and PD-L1 expression.

      4c3880bb027f159e801041b1021e88e8 Result

      In this ongoing analysis, BEP included 31 patients. 5 patients (16%, 95% CI (5%, 34%)) had a MPR; all of which stained positive for PD-L1 by IHC using 22C3 (TPS≥1%) and SP142 (PD-L1 expression on ≥1% tumor cells (TC) and/or tumor infiltrating immune cells (IC)) at baseline. We observed significant increases in natural killer (NK) cells (p=0.005) and CD8+ T-cells (p=0.031) and a Th1-response related dendritic cell (DC) subpopulation (p=0.031) and significant decreases in B-cells (p=0.015) after treatment.

      Patients who achieved MPR show lower baseline levels of degranulated CD8+ T-cells (p=0.015), late-activated NK-cells (p=0.043), memory CD4+ (p=0.048) and memory CD8+ T-cells (p=0.032); changes in PB NK-cells (p=0.041), a decrease in M-MDSCs and a Th-2 and Th-17-response related DC subpopulation (p=0.043) in response to treatment were noted in patients with MPR versus non-MPR.

      Among the 16 patients with TC/IC 1/2/3 (> 1% PD-L1 expression) the following significant differences were observed compared to TC0/IC0 (7 patients): higher levels of late-activated CD4+ T-cells (p=0.025) and mid-activated CD8+ T-cells (p=0.044) at baseline, decrease of senescent T-cells (p=0.041), monocytic myeloid-suppressor cell subpopulations (M-MDSCs) and an increase in a Th1-response related DC subpopulation (p=0.026) after treatment.

      TCR clonality analysis showed expansions in Vß-subtypes after atezolizumab treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immunophenotyping and TCR-Vß-repertoire analysis in peripheral blood samples from NSCLC patients treated with neoadjuvant atezolizumab show differences in immune cell subsets in baseline samples and changes after treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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      MA16.04 - Clinical and Molecular Characteristics of EGFR Mutant Lung Cancers with Concurrent TP53 and RB1 Mutations. (ID 12513)

      13:55 - 14:00  |  Author(s): Mark G Kris

      • Abstract
      • Presentation
      • Slides

      Background

      20% of patients with metastatic lung adenocarcinoma have activating EGFR-mutations. EGFR-mutant lung cancers can undergo histologic transformation to small cell lung cancer (SCLC) as a response to the selective pressure of EGFR-TKIs in <5% of patients after earlier-generation EGFR-TKIs and have been reported after osimertinib. SCLC nearly universally harbor TP53/RB1-alterations which are rarely seen in EGFR-mutant lung adenocarcinomas. We sought to identify this subset of patients, describe their clinical course and likelihood of SCLC transformation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective review of targeted next generation sequencing (NGS, MSK-IMACT) at Memorial Sloan Kettering (MSK) was performed to identify patients with concurrent EGFR-activating mutations and TP53/RB1-mutations within the same tumor sample from NGS between April 2014 to February 2018 with a data cutoff of March 2018. For comparison, consecutive patients with lung cancers harboring EGFR-mutations who were EGFR-TKI naïve and TP53/RB1-wildtype were also collected during that time-period.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 21% of lung cancer patients with activating EGFR-mutations (759/3662), 5% (40/759) had concurrent TP53/RB1-mutations. 43% (17/40) were female, 58% former-smokers (23/40, median pack-years: 8), and median age of 68 (range 25-86 years). 88% (35/40) were adenocarcinoma at diagnosis, of which 11% (4/35) transformed to SCLC during treatment; 10% (4/40) were de-novo SCLC at diagnosis, and 1 was large cell neuroendocrine. The transformation rate was significantly higher compared to previous work from MSK evaluating EGFR-mutant patients showing 4% (4/155) transformation (p=0.04). Concurrent PIK3CA mutations were more frequently seen in the EGFR/TP53/RB1 mutant group compared to the TP53/RB1-wildtype group (17% (n=6/35) vs 7% (n=4/60), p=0.11). 20 patients were EGFR TKI-naïve at the time of NGS; the median time on EGFR-TKI (ToT) was 7.6 months versus 14.2 months in the TP53/RB1-wildtype group (HR 4.48, p=0.0003). The overall survival (OS) of this cohort versus TP53/RB1-wildtype was not different (4.3 vs 4.1 years, HR 1.35, p=0.51). In the 4 patients with SCLC transformation, the median time to transformation was 2.4 years after a median of 1.5 EGFR-TKI therapies (range 1-5 lines). Median OS from time of transformation was 7 months. 63% (25/40) of the EGFR/TP53/RB1-mutant cohort had brain metastases during their disease course as compared to 50% (n=30) in the TP53/RB1-wildtype group (p=0.30).

      8eea62084ca7e541d918e823422bd82e Conclusion

      SCLC transformation is enriched in EGFR/TP53/RB1-mutant lung cancers, occurring in 11% of patients. Once SCLC transformation occurs, overall survival is short. Patients with EGFR/TP53/RB1 have a shorter time on EGFR-TKI. Further investigation into optimal treatment for this subset of EGFR/TP53/RB1 mutant lung cancers is critical.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • 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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      P1.01-74 - MET Exon 14-Altered Lung Cancers: Central Nervous System (CNS) Metastases and Patterns of CNS Progression on MET Inhibition. (ID 14263)

      16:45 - 18:00  |  Author(s): Mark G Kris

      • Abstract
      • Slides

      Background

      MET exon 14 (METex14) alterations are targetable drivers found in 3-4% of lung cancers. The frequency of intracranial disease and patterns of central nervous system (CNS) progression on MET tyrosine kinase inhibitors (TKI) are not well characterized.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced METex14-altered lung cancers identified by next-generation sequencing (MSK-IMPACT) between January 2014 and March 2018 were eligible for analysis. A retrospective review of clinical features, patterns of metastases, and CNS progression on MET-TKI was performed. The frequency of intracranial disease was compared to cohorts single-center of EGFR-mutant (n=200), ERBB2-mutant (n=98) and KRAS-mutant (n=200) lung cancers.

      4c3880bb027f159e801041b1021e88e8 Result

      82 patients with metastatic METex14-altered lung cancers were identified. The median age was 73; 56% (n=46) were female and 54% (n=44) were former smokers. The frequency of brain metastases at baseline was 11% (n=9/82). The lifetime frequency of intracranial metastases from diagnosis of metastatic disease was 34% (n=28/82). By comparison, the frequency of brain metastases was 47% (94/200, p=0.05) with EGFR-, 47% (46/98), p=0.09) with ERBB2-, and 32% (64/200, p=0.78) with KRAS-driven tumors. 6% (n=5/82) of patients developed leptomeningeal disease. The overall survival (OS) of patients who developed intracranial disease on therapy compared to those who did not develop intracranial disease was not significantly different (HR 0.66, 95% CI 0.30-1.43, p=0.29). 51 patients received crizotinib, 26 of whom developed progressive disease. The frequency of intracranial (alone), intracranial and extracranial, and extracranial (alone) progression was 8% (2/26), 19% (5/26), and 73% (19/26), respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A third of patients with METex14-altered lung cancers develop intracranial disease. This proportion is lower than that seen in EGFR- and ERBB2-mutant lung cancers and comparable to KRAS-mutant lung cancers. The frequency of CNS failure on crizotinib was lower than expected compared to historical rates in ALK-rearranged lung cancers.

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • 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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      P1.13-43 - Molecular and Imaging Predictors of Response to Ado-Trastuzumab Emtansine in Patients with HER2 Mutant Lung Cancers: An Exploratory Phase 2 Trial (ID 14068)

      16:45 - 18:00  |  Author(s): Mark G Kris

      • Abstract

      Background

      Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate (ADC) that has demonstrated clinical activity in patients with HER2 mutant lung cancers, independent of HER2 protein expression. We hypothesize that the degree of HER2 homo- and/or heterodimerization may lead to preferential trastuzumab binding and internalization, and may serve as a predictor of response to HER2 ADC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with metastatic HER2 mutant lung cancers were enrolled in a phase 2 trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1. An expansion cohort included patients assessed using PERCIST, with pre-treatment 89Zr-trastuzumab PET/CT as correlative HER2-targeted imaging. HER2 mutation was identified by next generation sequencing (NGS), and tumors with adequate tissue were subsequently tested by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), quantitative protein mass spectrometry, as well as quantitative HER2-HER3 heterodimerization by fluorescence lifetime imaging microscopy - Förster resonance energy transfer (FLIM-FRET).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 35 patients with HER2 mutant lung cancers were treated across 2 cohorts. ORR was 44% (8/18, 95% CI 22-69%) for RECIST cohort, and 46% (6/13, 95% CI 19-75%) for PERCIST cohort with 4 patients awaiting response assessment. Responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F, L755P). Concurrent HER2 amplification was observed in 6 of 35 (17%) patients by either NGS or FISH. IHC ranged from 0 to 3+ and did not predict response. HER2 protein expression was low or absent in 15/18 cases tested by mass spectrometry. HER3 overexpression was seen in 7/18 cases tested and among them 5/6 evaluable patients had a partial response. FLIM-FRET efficiency was tested positive for HER2-HER3 heterodimer, which has been shown to be affected by the symmetrical heterodimer interface mutations (Claus et al, 2018), in 3 patients thus far and 1 of them had a partial response. Pre-treatment 89Zr-trastuzumab PET/CT showed increased uptake in 3/8 patients tested to date, and all 3 patients subsequently had partial metabolic response.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study confirmed the efficacy of ado-trastuzumab emtansine in patients with HER2 mutant lung cancers. HER2-containing dimers as indicated by HER3 overexpression or FLIM-FRET efficiency, and HER2-targeted imaging with 89Zr-trastuzumab PET/CT, may predict response to HER2 ADCs.

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