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Charles M. Rudin



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    LA01 - IASLC Lectureship Award Session (ID 989)

    • Event: WCLC 2018
    • Type: Lectureship Award Session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 105
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      LA01.03 - Heine H. Hansen Lectureship Award for Small Cell Lung Cancer - New Opportunities in Small Cell Lung Cancer (ID 14724)

      13:50 - 14:00  |  Presenting Author(s): Charles M. Rudin

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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      MA15.02 - Long-Term Safety and Clinical Activity Results from a Phase Ib Study of Erlotinib Plus Atezolizumab in Advanced NSCLC (ID 12095)

      13:35 - 13:40  |  Presenting Author(s): Charles M. Rudin

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with EGFR mutation–positive non-small cell lung cancer (NSCLC) achieve favorable outcomes with EGFR tyrosine kinase inhibitors (TKIs); however, the long-term efficacy of these agents is limited by development of acquired resistance. Atezolizumab (anti–PD-L1 mAb) monotherapy has shown tolerability and durable clinical activity in NSCLC. By selectively targeting PD-L1 to block its interaction with receptors PD-1 and B7.1, atezolizumab can reinvigorate anti-cancer T-cell activity. Thus, combining atezolizumab and erlotinib could result in improved anti-tumor immunity and durable anti-tumor effects. Safety and preliminary clinical activity from a Phase Ib study of erlotinib plus atezolizumab in locally advanced or metastatic NSCLC have been previously reported (Rudin, et al. WCLC 2016). Here we describe updated findings from this study (NCT02013219).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      EGFR TKI-naive patients with NSCLC were enrolled into a safety-evaluation stage (Stage 1) regardless of EGFR status, and an expansion stage (Stage 2) enrolled patients with EGFR-mutant NSCLC who were previously untreated or treated with 1 prior non–EGFR TKI therapy. A 7-day run-in period with erlotinib 150 mg PO QD was followed by addition of atezolizumab 1200 mg IV q3w. The primary endpoint was safety/tolerability of the combination; secondary endpoints included clinical activity per RECIST v1.1.

      4c3880bb027f159e801041b1021e88e8 Result

      At data cutoff (August 18, 2017), 28 patients (Stage 1, n = 8; Stage 2, n = 20) were evaluable for safety, and the median survival follow-up was 26.0 months (range, 7.8-32.9; Stage 2). The median age was 61 years (range, 47-84), and the most common EGFR mutation was exon 19 deletion (44%). Grade 3 treatment-related AEs (TRAEs) were reported in 43% of patients; no Grade 4 or 5 TRAEs occurred. The most common TRAEs were increased ALT, pyrexia, rash and diarrhea (2 patients each). Serious AEs occurred in 54% of patients; treatment-emergent AEs led to atezolizumab discontinuation in 18% and erlotinib discontinuation in 11%. Clinical activity was evaluated in Stage 2 patients. ORR was 75% (95% CI: 50.9, 91.3), with a median DOR of 16.7 months (range, 4.2-26.0+). Median PFS was 15.4 months (95% CI: 8.4, not estimable [NE]), and median OS was 32.7 months (95% CI: 32.7, NE).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Atezolizumab plus erlotinib demonstrated a tolerable safety profile and compared favorably with prior reports of efficacy with erlotinib monotherapy. OS data are expected to mature and improve with longer follow-up; updated clinical and biomarker data will be presented. Further investigation of the combination is warranted to assess its full potential.

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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): Charles M. Rudin

      • 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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    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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      MA19.09 - Concurrent Mutations in STK11 and KEAP1 is Associated with Resistance to PD-(L)1 Blockade in Patients with NSCLC Despite High TMB (ID 11983)

      16:10 - 16:15  |  Author(s): Charles M. Rudin

      • Abstract
      • Presentation
      • Slides

      Background

      Targeted next generation sequencing (NGS) testing for lung cancer patients identifies recurrent patterns of co-mutations. STK11 is known to be associated with poor outcomes with immunotherapy. We have identified that STK11 is commonly co-mutated with KEAP1, but the impact of this pattern of co-mutation on response to immunotherapy is not known.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified 308 patients with advanced lung cancer treated at Memorial Sloan Kettering Cancer Center who underwent NGS testing with MSK-IMPACT and received at least one dose of PD-(L)1 inhibitor. Progression free survival (PFS) and overall survival (OS) from treatment initiation of PD-(L)1 blockade were calculated using Kaplan-Meier methodology and compared using logrank method and t-test for continuous variables.

      4c3880bb027f159e801041b1021e88e8 Result

      In a cohort of 308 patients with NSCLC treated with PD-(L)1 blockade, STK11 or KEAP1 mutations occurred frequently (23% and 22% respectively) and concurrent STK11 and KEAP1 mutations (STK11mut/KEAP1mut) were common (56% of all STK11 mutant patients and 13% of all lung cancers, Fisher’s test of association p<0.0001). Other common co-mutations with STK11 included KRAS (50%) and TP53 (48%). STK11mut/KEAP1mut patients had higher TMB than STK11wt/KEAP1wt patients (median 9.4 vs 6.1, Mann-Whitney p= 0.0002).

      STK11mut/KEAP1mut (n=39) patients had diminished PFS and OS compared to patients with STK11wt/KEAP1wt (n=210) (PFS HR 1.5, p=0.02; OS HR 2.3, p=0.001). As context, outcomes in STK11mut/KEAP1mut patients were similarly poor to EGFR mutant patients (n=28) treated with PD-(L)1 blockade (PFS p=0.7) despite substantially different tumor mutation burden (9.4 vs 4.9 mut/Mb, p<0.0001). Among STK11mut/KEAP1mut patients, poor outcomes were unchanged irrespective of KRAS status (PFS p=0.8, OS p=0.5). Patients with mutations in STK11 alone (n=31) or KEAP1 alone (n=28) had outcomes that more closely mirrored STK11wt/KEAP1wt patients (PFS p=0.9 and 0.1 respectively, OS p=0.1 and 0.2 respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      KEAP1 plus STK11 co-mutation is a common event in NSCLC that is distinctly associated with poor outcomes with PD-(L)1 blockade despite otherwise favor molecular features.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA22 - New Therapeutics, Pathology, and Brain Metastases for Small Cell and Neuroendocrine Tumour (ID 925)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 206 BD
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      MA22.01 - PARP Inhibitor Radiosensitization of Small Cell Lung Cancer Differs by PARP Trapping Potency (ID 13358)

      15:15 - 15:20  |  Author(s): Charles M. Rudin

      • Abstract
      • Presentation
      • Slides

      Background

      Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in six SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. The dose modification factor (DMF), defined as the ratio of RT dose needed to achieve an equivalent level of survival with RT alone compared to that for RT plus drug, was calculated at 37% survival. Phosphorylated gH2AX sub-nuclear foci were assessed by immunofluorescence to quantify double-stranded DNA breaks (DSBs). Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models.

      4c3880bb027f159e801041b1021e88e8 Result

      Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays with a talazoparib dose of 20 nM demonstrating a DMF ranging from 1.61 – 2.88 in 4 cell lines with 0.2 nM demonstrating a DMF of 1.56 in 1 additional cell line. We confirmed radiosensitization in 3 of 3 cell lines by CSAs with DMF ranging from 1.40 – 2.20. To determine effects of PARP trapping on radiosensitization, we identified that concentrations of 200 nM talazoparib and 1600 nM veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization (DMF 3.3 with talazoparib vs DMF 1.0 with veliparib). This observation further correlated with an increased number of DSBs induced by talazoparib as compared to veliparib, where we found that talazoparib produced more residual DSBs than veliparib and DMSO with IR (gH2AX foci mean per cell: talazoparib 53.5, veliparib 33.5, DMSO 25.5) and without IR (40.0, 19.6, 14.6). Finally, a dose of 0.2 mg/kg talazoparib in vivo caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PARP inhibition effectively sensitizes SCLC cell lines and PDXs to RT, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of RT in SCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MTE11 - Biology of Small Cell Lung Cancer (Ticketed Session) (ID 821)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 07:00 - 08:00, Room 203 BD
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      MTE11.02 - Biological Subsets of SCLC (ID 11565)

      07:30 - 08:00  |  Presenting Author(s): Charles M. Rudin

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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: 4
    • 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): Charles M. Rudin

      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-75 - Utility of cfDNA Testing for Acquired Resistance: The Memorial Sloan Kettering Experience with Plasma EGFR T790M Clinical Testing. (ID 12514)

      16:45 - 18:00  |  Author(s): Charles M. Rudin

      • Abstract
      • Slides

      Background

      Liquid biopsy for circulating tumor DNA (ctDNA) has been increasingly adopted for the detection of oncogenic drivers and drug resistance mechanisms. Practice guidelines for liquid biopsy are lacking and biologic factors influencing ctDNA detection and shedding are poorly understood. We evaluated factors influencing ctDNA detection, using EGFR-T790M as a case-study, in patients with acquired resistance to first/second-generation EGFR tyrosine kinase inhibitors (EGFR-TKI).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This single-center study included metastatic sensitizing EGFR-mutant lung cancer patients (exon 19 deletions, L858R, G719) who underwent plasma EGFR-T790M testing after acquired resistance to erlotinib, gefitinib, or afatinib between January 2016 and August 2017. Plasma T790M was performed by digital PCR. Variant allele fraction (VAF) was calculated as mutant/(wildtype+mutant) allele. Concordance between plasma and tissue testing was examined if tissue analysis (MSK-IMPACT and/or targeted PCR) occurred within 90 days of blood draw. Turnaround time (TAT) was measured from date of blood draw and/or biopsy to result. ctDNA results were correlated with metastatic site and the number of organs involved.

      4c3880bb027f159e801041b1021e88e8 Result

      177 patients underwent plasma T790M testing; 65% female, 47% current/former smokers. Plasma T790M was positive in 32% (56/177) of patients, tissue testing was T790M-positive in 46% (45/97), and overall T790M-positivity by either platform was 49% (86/177). The median TAT was shorter for plasma T790M compared to tissue PCR (9 vs 15 days, p<0.0001), and led to osimertinib use in 84% (47/56) of positive patients. Concordance between plasma and tissue T790M was 80% (32/40). 15 patients with positive plasma had matched tissue, 87% (13/15) were concordant on tissue. 76% (19/25) of the patients that were T790M-negative on plasma also tested negative on tissue. Median plasma T790M-VAF was 0.98% (range 0.1–49.5%), lower than tissue T790M-VAF (12.8%, range 2.58–27.8, p<0.0001). Plasma T790M-VAF did not correlate with time on osimertinib (p=0.72). Plasma T790M status correlated with a higher number of metastatic sites (4 vs 3, p<0.0001). Plasma T790M detection by organ sites were: pleura (58% with metastases vs 34% without metastases, p=0.14), bone (80% vs 21%, p=0.0002), hepatic (61% vs 41%, p=0.28), nodal (61% vs 33%, p=0.07), adrenal (64% vs 44%, p=0.60), brain (71% vs 38%, p=0.08), and bone/hepatic concurrently (94% vs 98%, p=0.04).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Using plasma T790M as an archetypal example, cfDNA testing showed concordance and a shorter turnaround compared to tissue testing. cfDNA was more likely to result positive in patients with more metastatic sites, or osseous and hepatic metastases possibly driven by increased ctDNA shedding.

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      P1.01-76 - A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Newly Diagnosed Stage IV Squamous Cell Lung Cancers (ID 13324)

      16:45 - 18:00  |  Author(s): Charles M. Rudin

      • Abstract

      Background

      Therapeutic options for SQCLC patients are limited. The efficacy of platinum-based doublets, long the standard first-line treatments, has plateaued, with ORR=30%. Anti-tumor synergy between gemcitabine and albumin-bound paclitaxel (ABP) was demonstrated by Frese et al. who showed that ABP downregulates cytidine deaminase, leading to increased intratumoral gemcitabine (Cancer Disc 2012). Based on these data, we sought to assess the efficacy of ABP + gemcitabine in patients with SQCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This was a Simon two-stage phase 2 study of ABP + gemcitabine in chemotherapy-naïve, PD-L1 low/unknown advanced SQCLC patients (NCT02525653). Primary endpoint: best ORR. H0=25% (≥6/17 responses) and HA=45% (≥16/41 responses). ABP (100mg/m2) + gemcitabine (1000mg/m2) was initially given on D1, D8, D15 of an every 4 week cycle for up to 6 cycles (A1). After clearing H0, the study was amended to a 3 week cycle (D1, D8 treatment) and to allow maintenance ABP after C4 (A2). All patients underwent NGS by MSK-IMPACT.

      4c3880bb027f159e801041b1021e88e8 Result

      N=27 patients were evaluable for the primary endpoint. Median age=70, age ≥70=60%, female=30%, median KPS=80%, smokers=93%. 46% of patients had PD-L1 IHC <50% (0-20%). 54% were PD-L1 unknown. Grade ≥3 related AEs included: fatigue-13%, neuropathy-4%; diarrhea-4%; lung infection-4%, anemia-9%; decreased platelet count-4%, and decreased neutrophils (4%). Four patients (17%) experienced related SAEs including, separately, G3 febrile neutropenia, G3 WBC decrease, G3 thrombocytopenia, and G3 anemia.

      ORR for the entire cohort was 63% (Figure 1). ORR in A2= 71% (10/14). 8 patients in A1 had dose modifications resulting in equivalency to the A2 schedule. ORR in the A2+A1 dose modified cohort=73% (16/22), meeting the primary endpoint early. Median PFS=8mo; OS not yet mature.

      15-054 waterfall.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      ABP + gemcitabine is an effective and well-tolerated regimen in patients with untreated advanced SQCLC with a response rate exceeding that associated with platinum regimens and first-line immunotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-99 - Detecting HER2 Alterations by Next Generation Sequencing (NGS) in Patients with Advanced NSCLC from the United States and China (ID 11285)

      16:45 - 18:00  |  Author(s): Charles M. Rudin

      • Abstract
      • Slides

      Background

      Advances in NGS have led to an increase in identifying specific actionable gene alterations across tumor types. We collected data on HER2 gene alterations detected by NGS from patients with advanced NSCLC and analyzed clinical characteristics and HER2 targeted treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients diagnosed with advanced NSCLC and underwent NGS testing from Jun 2014 to Dec 2017 at Memorial Sloan-Kettering Cancer Center (MSK) and Guangdong General Hospital (GGH) were included. NGS platforms were MSK-IMPACTTM in MSK and GeneSeek or BurnStone in GGH. Descriptive statistics are used in data analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      2200 patients from MSK and 490 patients from GGH underwent NGS testing. HER2 mutation and/or amplification were detected in 91/2200(4.1%) patients and 28/490(5.7%) patients from MSK and GGH respectively. Clinical characteristics were listed in Table1. 37.4%(34/91) and 21.4%(6/28) patients from MSK and GGH received HER2 targeted therapies. More patients were enrolled to HER2 inhibitors clinical trials in MSK(24.2%) than GGH(7.1%). The characteristics of HER2 alterations are summarized in Table2.

      Table 1. Comparison of HER2 alterations in advanced NSCLC patients from U.S. and China

      MSK

      N (%)

      GGH

      N (%)

      Total Patients

      91

      28

      Age at Diagnosis (years)

      <=60

      34 (37.4%)

      13 (46.4%)

      >60

      57 (62.6%)

      15 (53.6%)

      Sex

      Male

      37 (40.7%)

      14 (50%)

      Female

      54 (59.3%)

      14 (50%)

      Smoking History

      Former/Current Smoker

      53 (58.2%)

      7 (25%)

      Non-Smoker

      38 (41.8%)

      21 (75%)

      Histology

      Adenocarcinoma

      84 (92.3%)

      25 (89.3%)

      Squamous Cell Carcinoma

      5 (5.5%)

      0

      Misc

      2 (2.2%)

      3 (10.7%)

      HER2 status

      Mutation

      48 (52.7%)

      16 (57.1%)

      Amplification

      32 (35.2%)

      11 (39.3%)

      Mutation + Amplification

      11 (12.1%)

      1 (3.6%)

      HER2 targeted treatment

      34 (37.4%)

      6 (21.4%)

      Enrolled to HER2 inhibitors clinical trials

      22 (24.2%)

      2 (7.1%)

      Table 2. HER2 alteration in advanced NSCLC patients from U.S. and China combined

      NGS Result

      Mutation Only

      N (%)

      Amplification Only

      N (%)

      Mutation + Amplification

      N (%)

      Total Patients 64 43 12

      Age at Diagnosis (years)

      <=60

      31 (48.4%)

      20 (46.5%)

      8 (66.7%)

      >60

      33 (51.6%)

      23 (35.9%)

      4 (33.3%)

      Sex

      Male

      39 (60.9%)

      19 (44.2%)

      7 (58.3%)

      Female

      25 (39.1%)

      24 (55.8%)

      5 (41.7%)

      Smoking History

      Former/Current Smoker

      31 (48.4%)

      24 (55.8%)

      5 (41.7%)

      Non-Smoker

      33 (51.6%)

      19 (44.2%)

      7 (58.3%)

      Histology

      Adenocarcinoma

      58 (90.6%)

      39 (90.7%)

      12 (100%)

      Squamous Cell Carcinoma

      1 (1.6%)

      4 (9.3%)

      0

      Misc

      5 (7.5%)

      0

      0

      HER2 targeted treatment

      Yes

      19 (29.7%)

      14 (32.6%)

      7 (58.3%)

      No

      45 (70.3%)

      29 (67.4%)

      5 (41.7%)

      8eea62084ca7e541d918e823422bd82e Conclusion

      The incidence and clinical characteristics of HER2 alterations in advanced NSCLC were similar between two large cancer centers in the U.S. and China. These data support U.S.-China collaboration in clinical trials for patients with rare molecular subsets of NSCLC to accelerate new cancer drug development.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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): Charles M. Rudin

      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-44 - Targeting NFE2L2 Mutations in Advanced Squamous Cell Lung Cancers with the TORC1/2 Inhibitor TAK-228 (ID 12591)

      16:45 - 18:00  |  Author(s): Charles M. Rudin

      • Abstract

      Background

      Despite research efforts over the past decade, no targeted therapy options exist for patients with SQCLC. Analyses by TCGA and others (Paik Cancer Disc 2015) have identified a heretofore untargeted, frequently mutated oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~20% of patients with SQCLC. NFE2L2 encodes Nrf2, a transcription factor involved in the oxidative stress response which is targeted for degradation by Keap1. NFE2L2 mutations occur exclusively in an exon 2 hotspot that encodes the Neh2 domain (~aa.1-86), which is the binding site for Keap1. Mutations in this region disrupt Keap1 binding, leading to Nrf2 nuclear translocation and increased mTOR signaling through regulation of RagD (Shibata Cancer Res 2010). We now report translational studies and preliminary results from a phase 2 trial of the oral TORC1/2 inhibitor TAK-228 in SQCLC patients with these mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Cytotoxicity, signaling, and xenograft experiments were performed using LK-2 SQCLC cells harboring an NFE2L2 E79K mutation treated with TAK-228, everolimus, rapamycin, or deforolimus with requisite vehicle controls. Patients with stage IV SQCLC harboring NFE2L2 mutations were treated on an NCI CTEP- single-institution phase 2 study of TAK228 3mg po qd (continuous, 28 day cycles; NCT02417701). Primary endpoint: ORR. Secondary endpoints: PFS/OS. The study utilizes a Simon 2-stage design with H0=5% (N≥1/5 responses), HA=40% (N≥2/10 responses).

      4c3880bb027f159e801041b1021e88e8 Result

      TAK-228 exhibited significantly increased anti-tumor activity over TORC1 rapalogs in LK-2 cells. TAK-228 alone was cytotoxic at sub-[μM] (IC50 68nM); all other rapalogs exhibited IC50s >10μM. This was associated with an 80% decrease in downstream S6 phosphorylation. Tumor response (-55% shrinkage) was also seen in an LK-2 xenograft treated with TAK228. No anti-tumor/growth inhibitory response was seen with any other rapalog tested.

      N=4 patients have been treated on study (exon 2 del, D29H, F37V, W24C). 3 are evaluable for response. 2 related-SAEs (G3 hyperglycemia, G3 confusion) were seen; no other G3 AEs reported. ORR=67% (2 PR, 1 SD, 0 PD). Prolonged disease response is present, with DOR= 12mo, 10mo (ongoing), 8mo (ongoing).

      8eea62084ca7e541d918e823422bd82e Conclusion

      TAK228 is tolerable with evidence of pre-clinical and clinical activity in this biomarker-selected population. The trial has met its first-stage endpoint and has expanded to N=10 patients. The trial has also expanded to included patients with KRAS mutant lung cancers harboring co-alterations in NFE2L2 or KEAP1.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)

    • 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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      P3.12-06 - SLFN11 Expression and Efficacy of PARP Inhibitor Therapy in Extensive Stage Small Cell Lung Cancer: ECOG-ACRIN 2511 Study (ID 14113)

      12:00 - 13:30  |  Author(s): Charles M. Rudin

      • Abstract

      Background

      Veliparib (V),an oral small molecule inhibitor of poly (ADP) ribose polymerase (PARP) enhanced cytotoxic chemotherapy in preclinical models of small cell lung cancer (SCLC). The combination of V with cisplatin/etoposide (CE) doublet showed efficacy improvement as first-line therapy of extensive stage SCLC (ES-SCLC) with adjusted PFS HR: 0.63 1-sided p=0.01. There was differential treatment effect by strata (adjusted treatment HR comparing CE+V: CE: 0.34; 80% CI: 0.22 - 0.51; 1-sided p<0.001 for male patients with high tumor burden versus adjusted HR: 0.81 80% CI: 0.60 - 1.09; 1-sided p=0.18 for other patients subsets) highlighting the need to identify patient subset most likely to benefit. SLFN11 expression was previously shown to be associated with benefit of V when combined with temozolomide in relapsed SCLC and also predicted benefit of CE in preclinical models. We assessed the utility of SLFN11 as a predictive biomarker in the context of E2511 frontline clinical trial.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Archival tissue samples collected from patients with ES-SCLC enrolled and treated on E2511 study was employed for biomarker analysis looking at SLFN11 expression by immunohistochemistry. The study has 88% power to detect a PFS hazard ratio of 0.5 comparing SLFN11 (+) and (-) patients using a one-sided 0.025 level logrank test.

      4c3880bb027f159e801041b1021e88e8 Result

      There was an imbalance between control and experimental arms in the Male/abnormal LDH stratum (in strata) with respect to Age: p=0.006; malignant pleural effusion: p=0.095 and T stage: p=0.02. Median PFS was 5.1 mos on CE (95% CI 4.1-6.1) vs. 6.2 mos on CE+V (95% CI 5.9-8.8); HR=0.32, p=0.002 (unadjusted); median OS on CE was 8.8 mos (95% CI 6.6-11.1) vs. 9.5 mos on CE+V (95% CI 7.8-12.8); HR=0.76, p=0.39. Clinical outcome differences based on SLFN11 expression is ongoing and will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pending ongoing analysis of correaltion of biomarker with clinical outcomes

      6f8b794f3246b0c1e1780bb4d4d5dc53