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Justin F Gainor



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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.05 - Outcomes in NSCLC Patients Treated with First-Line Pembrolizumab and a PD-L1 TPS of 50-74% vs 75-100% or 50-89% vs 90-100% (ID 14358)

      14:00 - 14:05  |  Author(s): Justin F Gainor

      • Abstract
      • Presentation
      • Slides

      Background

      Among patients with NSCLC and a PD-L1 tumor proportion score (TPS) ≥50%, the response rate to the PD-1 inhibitor pembrolizumab is ~45%. Whether certain subsets of patients with a PD-L1 TPS ≥50% are more likely to benefit from treatment with a PD-1 inhibitor is currently unknown. We compared outcomes among NSCLC patients treated with first-line pembrolizumab and different PD-L1 TPS groupings: 50-74% vs 75-100% or 50-89% vs 90-100%.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed patients who received commercial pembrolizumab as first-line treatment for NSCLC with a PD-L1 TPS of ≥50% from the Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and Massachusetts General Hospital. Clinicopathologic characteristics and clinical outcomes were compared among patients with a PD-L1 TPS of 50-74% vs 75-100% or 50-89% vs 90-100%. Event-time distributions were estimated using Kaplan-Meier and compared with the log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      172 patients were identified for inclusion in this study. In the entire cohort, the overall response rate (ORR) to pembrolizumab was 33.9%, median progression-free survival (mPFS) was 4.8 months, and median overall survival (mOS) was 20.6 months. Compared to patients with TPS 50-74% (N=68, 39.5%), patients with TPS 75-100% (N=104, 60.5%) had a significantly higher ORR (45.2% vs 20.6%, P=0.001), a significantly longer mPFS (5.3 vs 2.5 mo, HR=0.61 [95% CI: 0.41-0.90], P=0.008), and a trend towards improved mOS (33.6 vs 20.6 mo, HR=0.60 [95% CI: 0.34-1.04], P=0.056). Compared to patients with TPS 50-89% (N=99, 57.6%), patients with TPS 90-100% (N=73, 42.4%) had a significantly higher ORR (50.7% vs 24.2%, P<0.001), a significantly longer mPFS (6.4 vs 2.8 mo, HR=0.52 [95% CI: 0.36-0.76], P<0.001), and a significantly longer mOS (33.6 vs 18.0 mo, HR=0.46 [95% CI: 0.27-0.79], P=0.008). There were no significant differences in smoking history, histology, sex, and age between patients in each TPS cutoff group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Among NSCLCs with a PD-L1 TPS ≥50% treated with first-line pembrolizumab, higher PD-L1 TPS levels above 75% and 90% are associated with improved clinical outcomes compared to NSCLCs with lower PD-L1 levels.

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    MA08 - Clinical Trials in Brain Metastases (ID 906)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 203 BD
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      MA08.05 - Brain Penetration of Lorlatinib and Cumulative Incidence Rates for CNS and Non CNS Progression from a Phase 1/2 Study (ID 12760)

      15:45 - 15:50  |  Author(s): Justin F Gainor

      • Abstract
      • Presentation
      • Slides

      Background

      The potent, selective, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) lorlatinib was designed to penetrate the blood-brain barrier (BBB). In a phase 1/2 study, lorlatinib showed robust clinical activity in patients with ALK-positive non-small cell lung cancer (NSCLC), most of whom had CNS metastases and failed ≥1 ALK TKI. In preclinical studies, lorlatinib demonstrated high BBB permeability with rapid brain uptake in vivo and significant activity against ALK-positive intracranial tumor models.1,2 To assess brain penetration of lorlatinib in a clinical setting, we report exploratory analyses from a phase 1/2 study (NCT01970865), evaluating CSF-to-plasma concentration ratios from a small sample of patients and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and deaths for pretreated patients with ALK-positive NSCLC ± baseline CNS metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Across the ongoing phase 1/2 study, 5 patients at lorlatinib 100 mg QD starting dose underwent CSF sampling. Patients with ALK-positive NSCLC with ≥1 prior ALK TKI were analysed for progressive disease, categorized as either CNS or non-CNS progression, based on independent central review. CIRs for patients in expansion cohorts EXP2–5 from the phase 2 portion of the phase 1/2 study (N=198) were calculated using competing risks methodology.

      4c3880bb027f159e801041b1021e88e8 Result

      In patients (n=5), mean CSF-to-plasma concentration ratio was 0.73 (SD 0.14). The table shows CIRs at 6 and 12 months.

      Months Cumulative Incidence Probability
      Patients with ≥1 prior ALK TKIa CNS Progression

      Non-CNS

      Progression

      		 Death
      All patients (n=198)

      6 mos

      12 mos

      0.13

      0.18

      0.25

      0.37

      0.05

      NE
      Patients with baseline CNS metastases (n=131)

      6 mos

      12 mos

      0.14

      0.22

      0.21

      0.31

      NE

      NE
      Patients with no baseline CNS metastases (n=67)

      6 mos

      12 mos

      NE

      NE

      0.32

      0.49

      0.05

      NE

      aPatients in expansion cohorts EXP2–5 from the phase 2 study

      NE, not evaluable
      8eea62084ca7e541d918e823422bd82e Conclusion

      Lorlatinib showed high BBB permeability as evidenced by a high mean CSF-to-plasma concentration ratio, in line with preclinical rat studies showing CNS penetration. This translated into high activity against CNS metastases as suggested by the numerically higher probability of the first progression event being extracranial rather than intracranial, including in patients with a history of CNS metastases.

      References

      1. Collier, et al. Mol Imaging 2017;16:1–3.

      2. Zou, et al. Cancer Cell 2015;28:70–81.

      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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      MA16.08 - Clinical Utility of Detecting ROS1 Genetic Alterations in Plasma (ID 13522)

      14:25 - 14:30  |  Author(s): Justin F Gainor

      • Abstract
      • Presentation
      • Slides

      Background

      ROS1-rearranged lung cancer harbors an oncogenic fusion protein created by the juxtaposition of the ROS1 gene to various fusion partners. Due to the lack of a conserved breakpoint and inclusion of intronic segments, ROS1 rearrangements can be challenging to identify with DNA-based sequencing approaches. The feasibility and clinical utility of detecting ROS1 fusions in circulating tumor DNA is not well established.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The Guardant360 de-identified database was queried to identify lung cancer cases with plasma ROS1 fusions and describe the molecular features of the ROS1-rearranged cohort. In addition, we performed longitudinal analysis of plasma specimens from four patients at our institution who were treated with next-generation ROS1 inhibitors after progressing on crizotinib.

      4c3880bb027f159e801041b1021e88e8 Result

      From review of 24,009 plasma specimens from lung cancer patients, we identified 56 patients with ROS1 fusions. CD74 was the most common of 7 identified fusion partners [n=35 (62%) CD74, n=7 (12.5%) SDC4, n=7 (12.5%) EZR, n=3 (5%) TPM3, n=2 (4%) TFG, and n=1 (2%) each of CCDC6 and SLC34A2]. ROS1 fusions commonly co-occurred with TP53 mutations (n=36, 64%) and genes involved in cell-cycle regulation (n=11, 20%) or the WNT/ß-catenin pathway (n=16, 29%). In 4 (80%) of 5 cases where plasma genotyping occurred at crizotinib progression, we identified a putative resistance mechanism, including a ROS1 resistance mutation in 3 patients (n=2 G2032R & n=1 L2026M) and a BRAF V600E mutation in 1 patient. We analyzed longitudinal plasma specimens from 4 patients with crizotinib-resistant lung cancer who were subsequently treated with a next-generation ROS1 inhibitor (n=3 lorlatinib, n=1 entrectinib). One patient treated with lorlatinib had a pretreatment ROS1 G2032R mutation (in plasma and tissue); plasma analysis revealed stability of the G2032R allelic fraction in the setting of primary progression of pleural disease. Of the 2 patients without pretreatment ROS1 mutations who received lorlatinib, one developed a ROS1 G2032R mutation after initial response to treatment. The second patient experienced primary progression and plasma genotyping revealed low level FGFR1 copy number gain (3.3 copies); pre-crizotinib plasma was not available for comparison. One patient had a plasma PIK3CA E545K mutation at the time of crizotinib progression, and did not respond to next-line entrectinib.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Next-generation sequencing can be used to detect ROS1 fusions and resistance mutations in plasma. Longitudinal plasma analysis may provide insight into the activity of investigational drugs against ROS1 mutations that mediate resistance to crizotinib.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.03 - Activity of Osimertinib and the Selective RET Inhibitor BLU-667 in an EGFR-Mutant Patient with Acquired RET Rearrangement (ID 14731)

      13:40 - 13:45  |  Author(s): Justin F Gainor

      • Abstract
      • Presentation
      • Slides

      Background
      The spectrum of acquired resistance (AR) to osimertinib is not yet fully characterized. We present a single-center cohort of osimertinib AR biopsies and results of a patient with RET-mediated AR treated with the investigational RET-specific TKI BLU-667 and osimertinib.
      a9ded1e5ce5d75814730bb4caaf49419 Method
      We assayed tissue via SNaPshot or Foundation One next-generation sequencing (NGS) and plasma via Guardant360 NGS under an IRB-approved protocol. In vitro studies assessed implications of RET fusions in EGFR-mutant cancers. We treated one patient with osimertinib/BLU-667 using an IRB and FDA-approved compassionate use protocol.
      4c3880bb027f159e801041b1021e88e8 Result
      41 EGFR-mutant patients with AR to osimertinib were assessed histologically and queried by tissue NGS (n=22), plasma NGS (n=9) or both (n=10). Key AR findings: SCLC transformation (2/32 tissue); EGFR C797S (5/32 tissue, 5/19 plasma, all cis with T790M); MET amplification (7/32 tissue, 3/19 plasma); BRAF rearrangement (2/32 tissue) and CCDC6-RET rearrangement (1/32 tissue, 1/19 plasma [distinct case]).
      CCDC6-RET was expressed in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells, which maintained MAPK signaling and conferred resistance to osimertinib and afatinib. Inhibition of RET by BLU-667 or cabozantinib resensitized cells expressing CCDC6-RET to EGFR inhibition.
      A 60-year-old woman with EGFR del19 progressed on afatinib (T790M+), then osimertinib. Tissue biopsy at osimertinib AR showed acquired CCDC6-RET (T790-wt). She began osimertinib 80mg/BLU-667 200mg daily x2 weeks, then BLU-667 was increased to 300mg daily. Her dyspnea improved within days of initiation. Scans after 8 weeks revealed a marked response with RECIST tumor shrinkage of 78% (Figure). She experienced only grade 1 toxicities of fatigue, leukopenia, hypertension, dry mouth, and elevated transaminases.
      8eea62084ca7e541d918e823422bd82e Conclusion
      RET rearrangements are rare but recurrent in EGFR-mutant patients with AR to osimertinib. In vivo models suggest they mediate AR and this patient provides proof-of-concept that combination EGFR+RET inhibition with osimertinib/BLU-667 is a well-tolerated and effective regimen for RET-mediated AR. Further study is ongoing.

      14731.jpg

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • 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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      P1.04-21 - The Utility of PD-L1/CD8 Dual Immunohistochemistry for Prediction of Response to Immunotherapy in Non-Small Cell Lung Cancer (NSCLC) (ID 13815)

      16:45 - 18:00  |  Author(s): Justin F Gainor

      • Abstract

      Background

      PD-L1 immunohistochemistry (IHC) is an important predictive biomarker for PD-(L)1 blockade in advanced non-small cell lung cancer (NSCLC); however, this assay is imperfect. The presence of CD8+ tumor infiltrating lymphocytes (TILs) may be a complimentary biomarker for response to immunotherapy. Thus, we examined the performance of PD-L1/CD8 dual IHC (dIHC) in two cohorts of NSCLC patients receiving immunotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were identified through retrospective review of medical oncology and pathology databases. The first cohort predominantly received nivolumab as a 2nd or later line treatment; tissue samples were mainly obtained at initial diagnosis. The second cohort received pembrolizumab as a first line therapy, and tissue samples were procured immediately before the initiation of immunotherapy. PD-L1/CD8 dIHC was performed on those tissue samples. Percentage of tumor cells with membranous PD-L1 expression and CD8+ stromal cells were measured, and CD8+ TILs were semi-quantitatively evaluated. The quantities of CD8+ T cells were dichotomized with appropriate cut-offs.

      4c3880bb027f159e801041b1021e88e8 Result

      Eighty-four patients were identified, including 60 in the Nivolumab cohort (NC) and 24 in the Pembrolizumab cohort (PC). In the NC, PD-L1 expression ≥1% was marginally associated with improved progression-free survival (PFS, p=0.09), and an increased rate of response (p=0.08). CD8+ TILs and stromal cells did not correlate with outcome. However, a subset of PD-L1-positive patients who showed abundant CD8+ TILs and stromal cells had significantly reduced PFS (p=0.04). In the PC cohort, all cases chosen exhibited PD-L1 expression in ≥50% of tumor cells. Increased CD8+ TILs were correlated with improved PFS, (p=0.0194), and an increase in both CD8+ TILs and stromal cells was also associated with improved PFS (p= 0.0238).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although limited by small sample size, this study suggests that PD-L1/CD8 dIHC improves the prediction of response to the PD-1/PD-L1 blockade in advanced NSCLC patients when it is performed on tissue samples obtained immediately before the initiation of the blockade as first-line therapy . However, for the 2nd or later line of treatment, dIHC on archival tissue samples obtained before initial therapy provides a useful but less clear picture of the tumor immune microenvironment. Reduced PFS seen in patients with PD-L1 expression and abundant CD8+ TILs and stromal cells may be due to T-cell exhaustion after the chemotherapy before the PD-1/PD-L1 blockade. These findings suggest that PD-L1/CD8 dIHC may be useful for treatment response stratification in advanced lung cancer patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • 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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      P2.04-23 - Immune-Related Adverse Events: The Growing Pains of Immunooncology (ID 14076)

      16:45 - 18:00  |  Author(s): Justin F Gainor

      • Abstract

      Background

      Immune checkpoint inhibitors (ICI) are associated with a distinct spectrum of toxicities, generally characterized as immune-related adverse events (irAEs). Despite increased recognition and improved management (mgmt), life-threatening toxicity affects a subset of pts. The Massachusetts General Hospital has created a novel inpatient oncology service, the severe ICI toxicity service (SIC), which aims to refine treatment of these irAEs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively identified pts with advanced thoracic malignancies who had received standard ICI (anti-PD(L)-1+/-CTLA-4 inhibition) and had been hospitalized for a grade ≥3 irAE. Demographic and clinical data were extracted from the medical chart and a descriptive analysis was performed.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 32 pts who required admission for toxicity mgmt. (Table 1). Average age on admission was 67yo (53-86) with an equal distribution between genders. Toxicity onset occurred at 101days (2-579) after the 1st ICI dose with 93.5% receiving anti-PD-(L)1 monotherapy. The most common irAEs were pneumonitis (35%), hepatitis (22%) and colitis (19%). 84% of pts received high-dose corticosteroids (1mg/kg) with 15% requiring a 2L immunosuppressant. In pts who completed a steroid taper, duration of use was 81d (42-192). The average length of stay was 8d (2-24) with 7pts requiring re-admission for toxicity flare. Eight pts (25%) experienced a grade 5 event (6 pneumonitis, 1 myocarditis, 1 hepatitis). Median PFS and OS were 6.3mths and 8.2mths, respectively.

      capture.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Severe irAEs requiring inpatient admission, though infrequent, result in considerable morbidity and mortality. Improved understanding of these toxicities and the mechanisms underlying their development is crucial. Novel academic efforts, such as the SIC service, are needed to fully characterize irAEs and ultimately develop novel therapeutic strategies to manage them.

      6f8b794f3246b0c1e1780bb4d4d5dc53