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Gregory J Riely



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    ES06 - New Approaches in Second Line Treatment In NSCLC (ID 9)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      ES06.03 - Future Strategies in Second Line Treatment (Now Available) (ID 3183)

      13:30 - 15:00  |  Presenting Author(s): Gregory J Riely

      • Abstract
      • Presentation
      • Slides

      Abstract

      With the continued refinement of molecularly targeted therapy and the dramatic changes in initial therapy for patients with newly diagnosed NSCLC without a molecular target, the concept of "second line" therapy has largely become outdated. For the more than one-third of patients who have a targetable oncogenic driver (with aberrations in genes such as EGFR [exon 19 deletion, exon 21 point mutation, or exon 20 insertion], ALK, ROS1, BRAF, RET, MET exon 14, or TRK), multiple lines of targeted therapy are possible prior to receiving a platinum-based combination chemotherapy combination (sometimes with the addition of an anti-PD-1/PD-L1 antibody). In such patients, "second line treatment" could actually be the fifth treatment regimen. Similarly, for patients with PD-L1 that is 50% or greater, the second-line treatment is typically platinum-based doublet chemotherapy. Practically, "second line treatment" is that given after a regimen that contains platinum-based chemotherapy. Despite the difficulties in defining second line treatment, it is an area with critical need for development of new treatments.

      Some new approaches to development of second line therapies are dependent upon a molecular evaluation of the patient’s tumor, typically selecting for targets that are not oncogenic drivers but rather other, non-driver, vulnerabilities found in a patient's tumor. This approach is best exemplified by the Lung MAP (Lung Cancer Master Protocol). This NCI-sponsored trial that began by enrolling only patients with squamous cell lung cancer but now enrolls patients with any NSCLC, uses the results of a comprehensive genomic profiling platform that looks at over 200 cancer-related genes for genomic alterations to assign patients to a genetically matched sub-study or randomize patients to an immunotherapy treatment. Cohorts have included patients with PI3KCA mutations receiving GDC-0032, patients with FGFR amplifications receiving AZD4547, patients with homologous repair deficiency receiving PARP inhibitors, and patients with STK11 alterations receiving talazoparib + avelumab. Critically, this trial uses staged evaluation of an arm to minimize the number of patients treated with relatively ineffective therapies.

      There is a great deal of interest in identifying new immunologic approaches for patients with NSCLC who have progressed after initial treatment with anti-PD-1/PD-L1 therapy. These approaches include the exploration of antibodies against such targets as the T-cell inhibitory receptor Tim-3 (T-cell immunoglobulin and mucin-domain containing-3) or small molecule inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1), a principle enzyme in tryptophan catabolism alone or in combination with anti-PD-1 or PD-L1 antibodies. Beyond this, there are attempts to improve the efficacy of single-agent anti-PD-1 antibodies by adding MEK inhibitors. Building off great successes in hematologic malignancies, there are new effort that seek to use cell-based therapies in patients with solid tumors. These include clinical trials of autologous T-cells that have been transduced with vectors expressing T-cell receptors against such targets as NY-ESO-1 and LAGE-1a for patients with NSCLC as well as trials exploring ex vivo expansion of tumor infiltrating lymphocytes.

      Treatment of patients who have progressed on available targeted therapies as well as platinum-based chemotherapies remains a notable challenge, with current treatments having limited activity. While none have yet proven effective, there are a broad array of treatments under study, whether using targeted therapies, chemotherapy combinations, or immunologic approaches.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-127 - Antitumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 in NSCLC with EGFR Exon 20 Insertions (ID 1302)

      09:45 - 18:00  |  Presenting Author(s): Gregory J Riely

      • Abstract
      • Slides

      Background

      We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor.

      Method

      Patients with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for patients with EGFR exon 20 insertions who received TAK-788 160 mg QD. Safety is reported for all patients across all doses and at 160 mg. To improve gastrointestinal tolerability, food intake instructions in this ongoing study were amended to allow for administration with or without a low-fat meal based on emerging clinical pharmacokinetic data in a healthy volunteer study (data on file).

      Result

      As of 14 Sep 2018, 101 patients (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5–180 mg QD. RP2D was determined to be 160 mg QD. 28 patients with EGFR exon 20 insertions were treated with 160 mg QD during dose escalation or in expansion cohort 1 (3.6 months on treatment; 3.8 treatment cycles [medians]); 24 patients remain on treatment. At data cutoff, best response (RECIST v1.1) among 26 patients with ≥1 disease assessment was PR, n=14; SD, n=9; and PD, n=1 (objective response rate, 54%; 95% CI: 33.4%–73.4%); 2 patients were unevaluable. 7/14 objective responses (all PR) were confirmed (6 awaiting confirmation; 1 unconfirmed PR at 160 mg QD); median time to response in these 14 patients was 56 days. 23/26 patients (89%; 95% CI: 69.9%–97.6%) achieved disease control. 23/24 evaluable patients with EGFR exon 20 insertions treated at 160 mg QD had decreased target lesion measurements (median best percent change, -32.6% [-79.1%–3.8%]). Most common TEAEs (≥20%) in patients treated with 160 mg QD: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), stomatitis (22%); grade ≥3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, stomatitis (7% each). Among patients treated with 160 mg QD, median dose intensity was 93%, rate of dose reduction due to AEs was 21.7%, and rate of treatment discontinuation due to AEs was 10.9%. There was no clear trend that response to TAK-788 was enriched in any single EGFR exon 20 insertion variant.

      Conclusion

      In NSCLC patients with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and a safety profile consistent with other EGFR TKIs.

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      P1.01-25 - Real-World Outcomes of Advanced NSCLC Patients with Common and Uncommon/Complex EGFR Mutation Profiles (ID 2387)

      09:45 - 18:00  |  Presenting Author(s): Gregory J Riely

      • Abstract

      Background

      In patients with advanced non-small cell lung cancer (aNSCLC) with non-squamous histology, the evaluation of EGFR mutations is standard of care and informs treatment selection. EGFR mutations are well-defined and can be classified into common, uncommon/complex mutation subtypes that are known to have different response rates to approved EGFR tyrosine kinase inhibitors (TKIs).

      Method

      We used data from the nationwide Flatiron Health electronic health record-derived database in this study. Our retrospective cohort included patients diagnosed in the US from Jan-2014 to Mar-2018 who had a positive EGFR test at time of first-line (1L) therapy initiation. Patients with baseline EGFR T790M mutations (n=44) or variants of unknown significance were excluded. Demographics, clinical characteristics, 1L treatment duration, and overall survival outcomes were compared between patients with common (Exon 19 E746-A750 del, Exon 19 del other, or Exon 21 L858R) vs. uncommon/complex EGFR mutations (all other EGFR mutations [i.e. Exon 18 G719X, Exon 20 insertions, Exon 21 L861Q], and/or concomitant mutations [KRAS, BRAF]). Minimum follow-up after initiation of 1L therapy was 4 months.

      Result

      23,321 patients had non-squamous or NOS histology. 1,315 patients had EGFR mutations detected prior to or during 1L treatment. Of those, 1,000 (82% common, 18% uncommon/complex mutations) had 1L EGFR TKI therapy initiated (median age 70 years, 70% women, 57% Caucasian, 47% smokers). In this population, 1L median treatment duration was longer for patients with common mutations than for those with uncommon/complex mutation profiles (11 vs 7 months; p<0.0001). Median overall survival was also affected by mutation status (24 vs 15 months; unadjusted HR 1.6; 95% CI 1.3–2.1; p<0.001). Among 315 patients (59% common, 41% uncommon/complex mutations) who initiated 1L treatment with non-EGFR TKI systemic therapies (median age 68 years, 59% women, 57% Caucasian, 53% smokers), median overall survival also improved with common vs uncommon/complex mutations (30 vs 17 months; unadjusted HR 1.7; 95% CI 1.3–2.4; p<0.001). However, there were no significant differences in median 1L (non-EGFR TKI) treatment duration (4 months common vs 6 months uncommon/complex mutations). Notably, 60% of patients with a common mutation treated with other 1L systemic therapies went on to receive a 2L EGFR TKI.

      Conclusion

      Uncommon/complex mutations were present in over 20% of aNSCLC patients with any EGFR mutations. Increased overall survival and 1L treatment duration with EGFR TKI therapy were observed in patients with common mutation subtypes vs. uncommon/complex mutation subtypes.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-39 - Molecular Characteristics, Immunophenotype, and Immune Checkpoint Inhibitor Response in BRAF Non-V600 Mutant Lung Cancers (ID 1529)

      09:45 - 18:00  |  Author(s): Gregory J Riely

      • Abstract
      • Slides

      Background

      Targeted therapy for Class I BRAF mutant lung cancers (V600) is well described and there is growing literature on their response to immune checkpoint inhibitors (ICI). In contrast, the molecular characteristics, immunophenotype, and response rates of class II and III BRAF mutations are not well defined.

      Method

      Patients with BRAF Class I, II, III mutant and variants of unknown significance (VUS) lung cancers detected on NGS (MSK-IMPACT) from 1/2014-1/2018 were identified. PD-L1 by immunohistochemistry (E1L3N) was evaluated. Tumor mutation burden (TMB; mut/Mb) was determined by MSK-IMPACT. Best objective response to ICI was assessed by RECIST v1.1. Time to treatment discontinuation (TTD) and overall survival (OS) were assessed. Statistical analysis was performed with Fisher’s exact and Kaplan-Meier. BRAF V600 lung cancers were used as a comparator and analyzed separately from BRAF non-V600.

      Result

      6.0% (177/2962) of lung cancers harbored a BRAF-mutation. Median TMB of BRAF non-V600 mutant lung cancers was 10.8 mut/Mb (n=136) overall compared to 4.9 mut/Mb in V600 (n=41; p<0.0001) and 5.9 mut/Mb in BRAF wild-type patients (n=2785; p<0.0001). 69% (127/177) of BRAF-mutant cases were metastatic (29 Class I, 36 Class II, 23 Class III, and 39 VUS). 57% of patients were female, 82% were smokers, and 90% were adenocarcinoma. More smokers were seen in the BRAF V600 group than in the non-V600 group (n = 16 vs 88 respectively, p<0.0001). PD-L1 expression in 49 non-V600 cases with available tissue was 0%, 1-49%, and >50% in 59% (n=29), 31% (n=15), and 10% (n=5) respectively. 7 BRAF V600 cases with PDL1 testing had expression of 0%, 1-49%, and >50% in 2, 3, and 2 cases, respectively. No BRAF V600 cases had concurrent RAS/NF1-alterations compared to 11 non-V600 (p=0.07).

      36 patients with BRAF non-V600 mutations received ICI (nivolumab (n=25), pembrolizumab (n=5), atezolizumab (n=2), ipilimumab/nivolumab (n=4); median line of therapy=2) with an ORR of 22% (8/36). 10 BRAF V600 mutant lung cancer patients received ICI (nivolumab (n=5), pembrolizumab (n=2), atezolizumab (n=1), ipilimumab/nivolumab (n=2); median line of therapy=2) with an ORR of 10% (1/10). There was no difference in ORR between non-V600 and V600 patients that received ICI (p=0.66). TTD in BRAF non-V600 was 3.2 months compared to 1.4 months for BRAF V600 mutant lung cancer patients (HR 0.59, p=0.26). Median TMB in patients with BRAF non-V600 mutations that responded vs those who did not was 13.2 and 10.8 mut/Mb respectively (p=0.92). One response to ICI was seen in a BRAF V600 with TMB of 19.3. OS of BRAF non-V600 patients was 1.7 years compared to 2.5 years in V600 (HR 1.25, p=0.38). OS was higher in BRAF non-V600 lung cancer patients who received ICI (2.4 years) compared to those that did not (1.2 years; HR 0.60, p=0.04).

      Conclusion

      The molecular characteristics and immunophenotype of BRAF non-V600 mutant lung cancers is typified by high TMB and low PD-L1 expression, with reasonably higher response rates and improved OS to later line ICI compared to BRAF V600. Further studies of immunotherapy in this oncogene subset is warranted.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-06 - Tissue-Based Molecular and Histologic Landscape of Acquired Resistance to Osimertinib in Patients with EGFR-Mutant Lung Cancers (ID 1392)

      09:45 - 18:00  |  Author(s): Gregory J Riely

      • Abstract
      • Slides

      Background

      Even though osimertinib (osi) is now the initial treatment for patients with EGFR-mutant lung cancers, our knowledge about mechanisms of resistance (MOR) is largely derived from patients who received osi after acquiring EGFR T790M on treatment with another EGFR inhibitor. Other studies of osi resistance have mainly reported genotyping of plasma which suboptimally detects lineage plasticity, copy number changes, and chromosomal rearrangements.

      Method

      To identify MOR to osi and characterize clinical, molecular and histologic factors associated with duration of response, we identified patients with EGFR-mutant lung cancers who had targeted next-generation sequencing (MSK-IMPACT) performed on tumor tissue obtained before treatment and after developing resistance to osi received as either first-line or later line EGFR-TKI.

      Result

      From January 2016 to March 2019, we collected paired pre-treatment and resistance specimens from 53 patients (1st line osi: 21. Osi after prior TKI: 32). MOR are summarized in the table. Histologic transformation was identified in 18% of 1st line cases and 17% of all cases. When osi was given as initial treatment, with median follow up of 18 months, early emerging MOR rarely included on-target resistance mechanisms (acquired EGFR G724S in 1/21). Other acquired alterations representing potential resistance mechanisms not listed in the table included CCNE1 and MYC amplifications, and mutations in MTOR A1098S and MET H1094Y.

      First line (n = 21)

      Osi after prior TKI

      (n = 32)

      All

      (n = 53)

      Squamous transformation

      3

      3

      6

      Neuroendocrine transformation

      1

      2

      3

      On target mutation (EGFR C797X or other)

      1

      9

      10

      Loss of EGFR T790M only

      -

      8

      8

      Fusions (ALK, RET, BRAF)

      0

      3

      3

      Amplifications (HER2, MET, EGFR)

      2

      3

      4

      Off target mutations (KRAS, BRAF, HER2)

      1

      2

      3

      Conclusion

      In this analysis of MOR identified on NGS from tumor tissue, we found a spectrum of resistance mechanisms to osi. By evaluating tissue rather than plasma we provide data on histologic transformation (including squamous cell transformation). Subsequent studies are needed to assess patients with a longer time on initial osi as early progressors may have different MOR, with off-target MOR emerging earlier and on-target resistance mutations later.

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      P1.14-12 - A Novel Activating MAP2K1 In-Frame Deletion Mediates Acquired Resistance to ROS1 TKIs in a Patient with ROS1 Fusion-Positive NSCLC (ID 2450)

      09:45 - 18:00  |  Author(s): Gregory J Riely

      • Abstract

      Background

      ROS1 tyrosine kinase inhibitors (TKIs) such as crizotinib, entrectinib and lorlatinib provide significant benefit in non-small cell lung cancer (NSCLC) patients with ROS1 fusions. As observed with all targeted therapies however, resistance arises. With the widespread adoption of large panel next generation sequencing (NGS) at the time of acquired resistance (AR), our appreciation of novel off-target mechanisms continues to grow. Detecting additional mechanisms of acquired resistance (AR) is crucial to find novel therapies and improve patient outcomes.

      Method

      We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) of paired pre-treatment and post-progression samples from patients treated with ROS1 TKIs. Genetic alterations hypothesized to confer AR were modeled in a patient-derived cell line (LUAD-0003, expressing EZR/ROS1) as well as isogenic human (HBEC) and murine (NIH-3T3) cell lines. ROS1 fusions were expressed in these cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). Using these cell line models, alterations in drug sensitivity and downstream signal pathways were examined. We also explored possible therapeutic strategies to overcome the drug resistance caused by the novel AR mechanisms examined in this study.

      Result

      We identified a patient with NSCLC harboring a MAP2K1 (MEK1) variant encoding an in-frame deletion of amino acids E41-L54 (MEK1del) in a sample taken at the time of resistance to lorlatinib (after 9 months’ treatment). This mutation was not detected in the pre-TKI sample. Induction of ROS1 fusions in HBEC and NIH-3T3 cells increased the sensitivity of these cells to ROS1 TKIs and stimulated activation of MEK/ERK signaling in comparison with AKT signaling, suggesting the importance of the RAS-MAPK pathway in driving ROS1 fusion-positive cancers. Underscoring the importance of the RAS-MAPK pathway in ROS1-mediated tumorigenesis, we identified three patients (pancreatic, salivary, and breast cancer) with a ROS1 fusion and NF1 loss-of-function mutation concurrently, in TKI-naïve samples. Expression of MEK1del in HBEC and NIH-3T3 cells harboring ROS1 fusions, and knockdown of NF1 in LUAD-0003, activated ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 (crizotinib, lorlatinib) and MEK (selumetinib, trametinib) inhibited growth of cells expressing both ROS1 fusion and MEK1del.

      Conclusion

      Our results suggest that the activation of the RAS-MAPK pathway plays a critical role in tumorigenesis mediated by ROS1 fusions, and that activating mutations in this pathway can drive AR to ROS1 TKIs. Combined inhibition of ROS1 and MEK is a potential therapeutic strategy that should be explored clinically.

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      P1.14-50 - A Phase 2 Trial of Cabozantinib in ROS1-Rearranged Lung Adenocarcinoma (Now Available) (ID 2753)

      09:45 - 18:00  |  Author(s): Gregory J Riely

      • Abstract
      • Slides

      Background

      To date, no ROS1 inhibitor is approved for the treatment of ROS1-rearranged lung cancers after progression on crizotinib. Progression on crizotinib can be mediated by the acquisition of ROS1 kinase domain mutations (e.g. ROS1G2032R or ROS1D2033N). Cabozantinib is a highly potent ROS1 tyrosine kinase inhibitor that has superior activity over lorlatinib against these mutations. We evaluated the activity of cabozantinib in patients with ROS1-rearranged lung cancers on a phase 2 trial.

      Method

      In this single-center, open-label, Simon two-stage, phase 2 study, eligible patients had ROS1-rearranged unresectable/metastatic non-small cell lung cancer, a Karnofsky performance status >70%, and measurable disease. ROS1 fusion was identified by local testing in a CLIA-compliant environment. Cabozantinib was dosed at 60 mg once daily. The primary endpoint was objective response (RECIST v1.1). In the first stage of this trial, 1 response was required to move to the second stage. Secondary endpoints included safety.

      Result

      Six patients received cabozantinib in the ongoing first stage of this study. All patients had >1 prior ROS1 inhibitor. The median age was 59 years; all were never smokers. The best response to therapy was: 1 partial response (-92%, confirmed), 1 unconfirmed partial response (-31%), and 4 stable disease. All patients had disease regression (-7 % to -92%); no patients had primary progressive disease. The only patient with a confirmed partial response was a patient whose cancer acquired a ROS1D2033N solvent front mutation after crizotinib. None of the other five ROS1 inhibitor pre-treated patients (who did not have a confirmed response) had a known on-target acquired resistance mutation in their cancer. After progression on cabozantinib (9.1 months after therapy initiation), the patient whose cancer harbored the ROS1D2033N mutation acquired a METD1228N kinase domain mutation on paired sequencing of pre-cabozantinib and post-progression tumor. The most common grade 3 treatment-related adverse events were hypertension (50%), and mucositis, palmar-plantar erythrodysesthesia, and hypophosphatemia (each in 17%). Most patients (83%) required a dose reduction.

      Conclusion

      Cabozantinib can re-establish disease control in ROS1-rearranged lung cancers after progression on a prior ROS1 inhibitor. The first stage of this ongoing trial met its prespecified endpoint for efficacy to move into the second stage. Response was only observed in the setting of a known ROS1 kinase domain resistance mutation.

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