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Karen L. Reckamp



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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Now Available
    • 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) (Now Available) (ID 12941)

      14:30 - 14:35  |  Author(s): Karen L. Reckamp

      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA01 - Improving Outcomes in Locoregional NSCLC I (ID 892)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 107
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      OA01.07 - Updated Results of a Phase II Trial of Concurrent Chemoradiation with Consolidation Pembrolizumab in Patients with Unresectable Stage III NSCLC (Now Available) (ID 13961)

      11:35 - 11:45  |  Author(s): Karen L. Reckamp

      • Abstract
      • Presentation
      • Slides

      Background

      Concurrent chemoradiation (CRT) has been the standard Rx for pts with unresectable stage III NSCLC. A recent phase III trial (PACIFIC) of consolidation durvalumab [PDL-1 inhibitor] demonstrated improved median PFS vs. placebo (16.8 vs. 5.6 mo, HR 0.52, p<0.001). 12-mo (55.9% vs. 35.3%) and 18-mo (44.2% vs. 27%) PFS were also improved. Toxicity was manageable with a grade 3-4 pneumonitis rate of 3.4%, and 4 patients experienced grade 5 pneumonitis. We report updated results of a phase 2 trial of consolidation pembrolizumab [PD-1 inhibitor] following concurrent CRT in patients with unresectable stage III NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      After completion of CRT with carboplatin/paclitaxel, cisplatin/etoposide, or cisplatin/pemetrexed + 59-66.6 Gy XRT, those pts w/o PD after 4-8 weeks off CRT received pembro 200 mg IV q3wk for up to 1 yr. The primary endpoint was time to metastatic disease or death [TMDD]. Key secondary endpoints included PFS, OS, and toxicity.

      4c3880bb027f159e801041b1021e88e8 Result

      93 pts enrolled [92 eligible for efficacy analysis]. Median f/u was 18.6 mo and median age 66 (45-84). 64.1% male and 35.9% female. Stages were 59.8% IIIA and 40.2% IIIB. 55.4% non-SqCC and 43.5% SqCC with 1 mixed histology. 94.6% were current/former smokers. Chemo regimens included carbo/pac (71.7%), cis/etop (26.1%), cis/pemetrexed (2.2%). Median number of cycles of pembro was 13.5 [1-19]. 16% received < 4 cycles; 84% received > 4 cycles; 37% completed 1 yr pembro. Median TMDD was 22.4 months (95% CI 17.9-NR). Median OS was NR (95% CI 22.4-NR), and the estimates of 1-yr and 2-yr OS were 81% and 61.9% respectively. Median PFS was 17 months (95% CI 11.9-NR). 12, 18, and 24-month PFS were 60.2%, 49.9%, and 44.6% respectively. 16 (17.2%) pts developed G2 pneumonitis, 5 (5.4%) had G3-4 pneumonitis. There was 1 pneumonitis-related death. In those developing G2 pneumonitis, the median time was 8.4 wks [1.1-48.3]. No other G 3/4 toxicities exceeded 5% except dyspnea (5.4%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Consolidation pembrolizumab following CRT substantially improves TMDD and PFS compared with historical controls. Prelim OS data is promising and suggests a substantial gain in outcomes of patients with stage III NSCLC is possible with consolidation pembrolizumab. These data will be updated further prior to the World Conference on Lung Cancer Meeting.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA12 - Novel Therapies in MET, RET and BRAF (ID 921)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
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      OA12.07 - Clinical Activity of LOXO-292, a Highly Selective RET Inhibitor, in Patients with RET Fusion+ Non-Small Cell Lung Cancer (Now Available) (ID 13922)

      16:20 - 16:30  |  Author(s): Karen L. Reckamp

      • Abstract
      • Presentation
      • Slides

      Background

      RET kinase gene fusions are actionable drivers that occur in ~2% of non-small cell lung cancers (NSCLC). However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET fusion+ NSCLC patients has been limited. LOXO-292 is a highly selective RET inhibitor, with preclinical activity against diverse RET fusions, potential acquired resistance mutations, and against brain metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LIBRETTO-001 is a multicenter global phase 1/2 study (26 sites, 9 countries) enrolling patients w/ advanced solid tumors (NCT03157128) including RET fusion+ NSCLC. Patients are dosed orally in 28-day cycles with dose escalation following a 3+3 design. The primary endpoint is MTD/recommended dose determination. Secondary endpoints include safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR). Initial data were presented at the ASCO 2018 Annual Meeting.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 02-April 18, 82 solid tumor patients (including 38 RET fusion+ NSCLC) were treated at 8 doses (20 mg QD-240 mg BID). The MTD was not reached. AEs (≥10% of patients) were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (11%); most were grade 1-2. 2 TEAEs ≥ grade 3 were attributed to LOXO-292 (Gr3 tumor lysis syndrome, Gr3 increased ALT). Of the 38 RET fusion+ NSCLC pts, 30 had at least 1 post-baseline assessment or discontinued LOXO-292 prior to such assessment. 26 of 30 patients (87%) had >20% radiographic tumor reduction (range: -21 to -72%). The ORR was 77% (23/30, 3 responses pending confirmation) with a confirmed ORR of 74% (20/27, excluding 3 patients with unconfirmed responses). The response rate was similar regardless of prior MKI treatment (12/15 MKI-naïve, 11/15 MKI pretreated). Responses occurred independent of upstream fusion partner when known (13/16 KIF5B vs 9/11 other) and included patients w/ baseline brain metastases. Most patients remained on treatment (33/38), including all responders. The median DoR was not reached (longest response was the first responder: >10+ months). Rapid plasma clearance of RET variants was observed, with complete clearance by day 15 in 10 of 17 (59%) NSCLC patients with assessable baseline and day 15 ctDNA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      LOXO-292 was well-tolerated and had marked antitumor activity in RET-fusion+ NSCLC patients, including those w/ resistance to prior MKIs and brain metastases. Phase 2 cohorts are now open globally (160 mg BID). Updated safety and efficacy data as of 19 Jul 2018 will be presented.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • 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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      P2.01-06 - HSP72 Expression Associates with Survival in EGFR Mutated NSCLC (ID 14285)

      16:45 - 18:00  |  Author(s): Karen L. Reckamp

      • Abstract

      Background

      Heat shock protein 72 (HSP72) was observed to be important for editing DNA replication errors and repairing base damage. EGFR mediates HSP72 Y41 stability via phosphorylation. EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy inhibited phosphorylation of HSP72 leads to its degradation with suppression of polymerase α (Polα) and a resultant increase in overall mutation rate in EGFR mutant lung cancer cells. Our primary objective was to determine if baseline HSP72 expression is a prognostic biomarker for NSCLC patients with EGFR mutant NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort of patients was identified with known EGFR mutation positive NSCLC and available tissue from the City of Hope Comprehensive Cancer Center seen between 2008 and 2016. Immunohistochemical (IHC) analysis was performed to analyze HSP72 levels. A chi-square test for categorical data and multivariate logistic regression analyses was used to study the relation between HSP72 expression and the other clinical and demographic data.

      4c3880bb027f159e801041b1021e88e8 Result

      48 patients with EGFR mutated NSCLC and available tissue were identified. The median age was 64 range (39-84) with 50% Asian (n = 24), Caucasian 38% (n = 18), and African American 8% (n = 4) and other 4% (n = 2). Most patients were Stage IV at initial diagnosis (n = 41, 85%), other were Stage IB (n = 2), Stage IIB (n = 1), Stage IIIA (n = 1) and Stage IIIB (n = 3). HSP72 expression was 0 in 16 patients, 1 in 15 patients, 2 in 9 patients and 3 in 8 patients. Median survival of HSP72 0, 1, 2,3 were 28.3, 42.4, 41.2, and 107.7 months respectively (p < 0.02, log-rank test). In univariate Cox regression analysis, HSP72 expression of 3 compared to others correlated with an HR of 0.23 (95% CI 0.07-0.77). When stratifying by stage (Stage IV vs all others), the HR associated with an HSP72 expression of 3 was 0.22 (95% CI 0.05-0.97), and the signal for HSP72 was also significant when stratifying by stage and considering HSP72 score as either a continuous marker or as the four categories (0,1,2,3). There was no relationship noted in the change in HSP72 values as tumors transformed from T790M- to T790M+, and no relationship related to L858R or exon 19 deletions.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In EGFR mutated NSCLC, high levels of HSP72 expression are associated with improved survival. Further investigations are evaluating mechanisms of increased DNA damage following EGFR TKI therapy and association with the development of resistance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PC04 - Targeted Therapy for NSCLC (ID 843)

    • Event: WCLC 2018
    • Type: Pro-Con Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 106
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      PC04.02 - Optimal Sequencing of EGFR TKI Therapy - 3rd Generation First (Now Available) (ID 11615)

      15:27 - 15:39  |  Presenting Author(s): Karen L. Reckamp

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is a heterogeneous genomic disease defined by molecular pathways that mediate oncogenesis which are often driven by genetic alterations and targeted therapies are available to modulate these pathways and improve patient outcomes.1 Non-small cell lung cancer (NSCLC) has been at the forefront of expanding knowledge of genomic alterations to inform therapeutic options that improve cancer patient outcomes. Signaling through the epidermal growth factor receptor (EGFR) can modulate multiple intracellualar pathways, including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-AKT, and signal transducer and activator of transcription proteins (STATs). Activating mutations in the epidermal growth factor receptor (EGFR) gene have been associated with improved progression free survival when patients are treated with EGFR tyrosine kinase inhibitor (TKI) therapy.1 Progress has been made in identifying these mutations and providing targeted therapy to improve outcomes for patients. Despite these advancements, tumors develop resistance and patients still succumb to the lung cancer, so overcoming the resistance became a priority. With the identification of third-generation EGFR TKIs, such as osimertinib,2 clinical benefit was maintained after tumor progression on first-generation EGFR TKIs, and questions regarding the optimal sequencing of EGFR TKIs emerged.

      Mutations in the TK domain of the EGFR gene demonstrate increase sensitivity to EGFR TKI in NSCLC.3,4 Gefitinib was the first EGFR TKI to demonstrate PFS benefit over chemotherapy as front line treatment of patients with EGFR mutant NSCLC.1 This was the first study to definitively identify mutation status as an important predictive marker for EGFR-TKI therapy and support molecular selection for patients with metastatic NSCLC. Multiple subsequent trials with gefitinib, erlotinib and afatinib confirmed enhanced PFS for front line EGFR TKI therapy.

      Developing appropriate therapies for EGFR-TKI-resistant disease requires a detailed understanding of mechanisms of resistance. Secondary mutations have been described that may arise that render initially sensitive tumors that harbor EGFR mutations, resistant to EGFR therapy. Multiple mechanisms of resistance have been identified, but approximately 50-60% of EGFR mutant NSCLC develops a T790M resistance mutation.5-7 Osimertinib was developed to overcome T790M resistance and block mutant EGFR while sparing wild type EGFR. Treatment following the development of T790M resistance led to improved objective response rates (ORR) and PFS for patients with EGFR mutant NSCLC.8 Early evidence suggested that osimertinib could be effective as first-line treatment,9 and had the potential benefit to prevent the most common cause of resistance. In the phase III FLAURA trial, 556 patients were randomized to osimertinib or standard, first generation EGFR TKI (erlotinib or gefitinib).10 The primary endpoint was progression free survival (PFS), and demonstrated an improvement for osimertinib at 18.9 months (95% CI, 15.2-21.4) compared to standard EGFR TKI at 10.2 months (95% CI, 9.6-11.1) with a hazard ratio (HR) 0.45 (95% CI, 0.37-0.57) and p< 0.001. The PFS for patients with central nervous system metastases remained higher for osimertinib at 15.2 months (95% CI, 12.1-21.4) compared to standard EGFR TKI at 9.6 months (95% CI, 7.0-12.4) with a hazard ratio (HR) 0.47 (95% CI, 0.30-0.74) and p< 0.001. The improvement of PFS in patients with brain metastases augments the clinical benefit to patients who may avoid or defer radiation treatments to the brain. Overall survival (OS) was immature with a trend toward improvement with osimertinib. ORR was similar in both arms, 80% (95% CI, 75-85) for osimertinib and 76% (95% CI, 70-81) for standard EGFR TKI therapy (95% CI, 70-81). These results have led to the US Food and Drug Administration approval of osimertinib as front line therapy for patients with advanced EGFR mutant NSCLC. Providing a drug with less toxicity and increased efficacy as a first-line option improves quality of life and outcomes for patients. New mechanisms of resistance will develop and must be overcome, but third-generation EGFR TKI therapy is now the new standard of care for front line therapy in metastatic EGFR mutation positive NSCLC.

      References

      1. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.

      2. Wakelee HA, Gettinger S, Engelman J, et al. A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. Cancer chemotherapy and pharmacology 2017;79:923-32.

      3. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39.

      4. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500.

      5. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240-7.

      6. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine 2011;3:75ra26.

      7. Ohashi K, Sequist LV, Arcila ME, et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A 2012;109:E2127-33.

      8. Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689-99.

      9. Ramalingam SS, Yang JC, Lee CK, et al. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2018;36:841-9.

      10. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25.

      e353dbe42c8654f33588d4da0b517469

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