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Rafael Santana-Davila



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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.07 - Phase I Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naïve Non-Small Cell Lung Cancer (JVDF) (Now Available) (ID 209)

      15:45 - 17:15  |  Author(s): Rafael Santana-Davila

      • Abstract
      • Presentation
      • Slides

      Background

      Emerging data suggest blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) with ramucirumab (R) and programmed cell death 1 protein (PD-1) with pembrolizumab (P) has anti-tumor activity. The JVDF study (NCT02443324) evaluated the safety and efficacy of R+P in locally advanced and unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma, non-small cell lung cancer (NSCLC), urothelial carcinoma, and biliary tract cancer. Data from NSCLC patients receiving R+P as first-line therapy are reported.

      Method

      Eligible patients had treatment-naïve, PD-L1 positive, histopathologically confirmed nonsquamous or squamous NSCLC and received R 10 mg/kg and P 200 mg on Day 1 every 21 days for up to 35 cycles until confirmed disease progression or discontinuation for other reasons. Response and progression were assessed using RECIST 1.1 with confirmatory scans. PD-L1 was assessed using the PD-L1 IHC 22C3 pharmDx assay; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥1%.

      Result

      As of August 31, 2018, 26 patients were treated. Baseline characteristics were as expected for an advanced, treatment-naïve population. Median follow-up was 17.4 (13.4, 20.1) months. Adverse events were consistent with R+P, with no additive toxicities. Eleven (42.3%) patients experienced Grade ≥3 treatment-related adverse events (TRAEs), most commonly hypertension (15.4%) and myocardial infarction (7.7%). No patients discontinued because of TRAEs; the two on-study deaths were due to disease progression. Efficacy results are shown in the table.

      table.jpg

      Conclusion

      In previously untreated NSCLC, R+P has a manageable safety profile and is active in patients with PD-L1 expression. Updated results will be presented at the meeting. Randomized trials in this population are warranted.

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    OA12 - Profiling the Multidisciplinary Management of Stage III NSCLC (ID 144)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      OA12.03 - Initial Reporting of NRG-LU001, Randomized Phase II Trial of Concurrent Chemoradiotherapy +/- Metformin HCL in Locally Advanced NSCLC (Now Available) (ID 1868)

      15:45 - 17:15  |  Author(s): Rafael Santana-Davila

      • Abstract
      • Presentation
      • Slides

      Background

      Preclinical and retrospective clinical data, have shown that metformin, an inexpensive diabetes drug, has the potential to improve response to chemotherapy and radiation in several solid tumors, including non-small cell lung cancer (NSCLC). These findings led to NRG-LU001, a multi-institutional, international randomized Phase II clinical trial to determine whether metformin can improve outcomes of curative chemoradiation (CRT) in locally advanced NSCLC (LA-NSCLC).

      Method

      Unresectable stage IIIA/B NSCLC patients were randomized to either concurrent chemoradiation to 60 Gy with weekly carboplatin-paclitaxel (CP), followed by consolidation CP (Control) or the same regimen combined with metformin (2000 mg/day) (Experimental). The primary endpoint was 1-year progression free survival (PFS). PFS and overall survival (OS) were estimated using the method of Kaplan-Meier. Time to loco-regional progression (TTLRP) or distant metastasis (TTDM) were estimated using the cumulative incidence method. Adverse events (AEs) were graded using CTCAE v4.0.

      Result

      170 patients were randomized between Aug. 2014-Dec. 2016, with planned analysis at 102 events. No significant difference in toxicity was observed between Control and Experimental arms. 1- and 2-year PFS was 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in Control vs 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the Experimental arm (multivariable Cox proportional HR=1.20 (95% CI: 0.81, 1.78), p=0.36). On multivariable analysis including treatment arm, performance status, histology and stage, only higher stage (IIIA vs. IIIB) was associated with worse PFS (HR 1.79, 95% CI:1.19, 2.69, p=0.0054). OS at 2 years was 65.4% (95% CI: 53.5, 75.0) for Control vs 64.9% (95% CI: 53.1, 74.5) for the Metformin arm (HR=1.03 (95% CI: 0.64, 1.68)), while deaths due to disease were 90% vs 71%, respectively. No significant differences were found for TTLRP (HR 1.01, 95% CI: 0.57, 1.79, p=0.98) or TTDM (1.38, 95% CI: 0.76, 2.5, p=0.29). 63.4% of patients in the experimental arm received the complete course of metformin, with the most common cause of discontinuation being side effects or complications (13.4%).

      Conclusion

      In NRG-LU001, concurrent CRT and metformin presented no noticeable safety concerns. However, this combination failed to improve PFS at the hypothesized effect size. Additionally, no effect on OS or patterns of failure were identified. Blinded central review of imaging based PFS is ongoing. Somewhat unexpectedly, 37% of patients did not complete the prescribed course of metformin. Additionally, deaths due to disease were less in the experimental arm compared to control.

      Acknowledgements: This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC). HS and TT are Co-Principal Investigators in this trial.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-27 - Duration of Targeted Therapy in Advanced NSCLC (aNSCLC) with Drivers Identified by Circulating Tumor DNA (ctDNA) Analysis (ID 953)

      09:45 - 18:00  |  Author(s): Rafael Santana-Davila

      • Abstract

      Background

      Identifying targetable genomic drivers is critical for optimal first-line treatment planning in aNSCLC. ctDNA testing can aid treatment selection when tissue specimens are inadequate for complete genotyping or when a rapid turnaround time is advantageous. Targeted therapy (TT) outcomes for ctDNA-detected drivers have not been widely reported in the first-line setting given the relatively recent adoption of this technology into clinical practice.

      Method

      We conducted a multicenter retrospective review of patients with aNSCLC who received matched TT following identification of a driver on a validated commercial ctDNA assay (Guardant360). Eligible patients were tested per regular clinical care between March 2014-October 2018 and must not have received a TT prior to ctDNA testing (prior chemotherapy or immunotherapy was permitted). Kaplan-Meier analysis was used to estimate median duration of TT (DTT) for both the first and all subsequent sequential targeted therapies where applicable (e.g. osimertinib following erlotinib). Patients still on TT were censored at last follow-up.

      Result

      76 patients met inclusion criteria. Median age of diagnosis of aNSCLC was 64.5 years (range 31-87y), 67% were female, 74% were never smokers, and 97% had adenocarcinoma histology. 21/76 (28%) patients received chemotherapy (n=17), immunotherapy (5), and/or a biologic (4) prior to receiving TT. 41/76 (54%) patients remain on TT at the time of data analysis, 32 of whom are still on their first TT. 38/41 patients still on TT have at least 6 months follow-up. Treatment outcomes are summarized in Table 1.

      Table 1. Duration of Targeted Therapy

      Driver

      Therapy

      n, total patients/discontinued therapy

      Median (95% CI) DTT in weeks1

      EGFR

      Erlotinib

      Osimertinib

      Afatinib

      Gefitinib

      Any EGFR TKI2

      21 / 19

      23 / 6

      3 / 2

      1 / 1

      48 / 20

      33 (23-54)

      NR

      3, 13, 93*

      63

      86 (48-197)

      ALK fusion

      Alectinib

      Crizotinib

      Any ALK TKI3

      7 / 2

      2 / 2

      9 / 2

      NR

      20, 44

      NR

      BRAF V600E

      Dabrafenib + Trametinib

      10 / 7

      51 (13-88)

      MET exon 14 skipping

      Crizotinib

      Investigational

      3 / 2

      1 / 1

      4, 77, 63*

      14

      ROS1 fusion

      Investigational

      2 / 1

      50, 79*

      ERBB2 exon 20 insertion

      Ado-trastuzumab emtansine

      2 / 1

      46, 14*

      RET fusion

      Investigational

      1 / 1

      47

      1 – individual data rather than median provided for counts <5

      2 – includes 15 patients receiving sequential EGFR TKIs

      3 – includes 3 patients receiving sequential ALK TKIs

      * indicates therapy is ongoing for individual data points

      Abbreviations: NR – not reached; TKI – tyrosine kinase inhibitor

      Conclusion

      This study provides interim data on targeted therapy outcomes for aNSCLC patients with Guardant360-detected drivers treated in everyday clinical practice. Outcomes are in line with what is expected for tissue-detected drivers in the TT naïve setting and this cohort will continue to be followed. Identification of NSCLC driver mutation using well-validated ctDNA assays can be used for clinical decision-making.