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  • Integrating Therapeutic Advances and Stakeholder Perspectives to NSCLS Clinical Pathways Discussions and Implementation

    This educational activity is supported by an educational grant from

    Genentech, and Novartis Pharmaceuticals Corporation

  • Faculty

    David Jackman, MDMedical Director of Clinical PathwaysSenior Physician Dana-Farber Cancer InstituteAssistant Professor Harvard Medical School

  • Disclosures

    Dr Jackman: Consultant AstraZeneca, Celgene, CVS, Eli Lilly

  • Learning Objectives

    Describe the current state of NSCLC care and the impact of recent advances in precision medicine on the diagnostic-treatment paradigm

    Outline the factors that contribute to variations in evidence-based practice, patient outcomes, and health-related costs in NSCLC diagnosis and management

    Evaluate the impact of NSCLC pathways on utilization, costs, outcomes, guideline adherence, personalized therapeutic selection, and inclusion of recent advances

    Apply strategies to improve adherence and mitigate barriers to NSCLC pathways within your institution

    Integrate the patient perspective into pathway development and discussions

  • Stakes & Stakeholders

  • Stakes

    What is the best care we can provide? Best care for the many and the individual Guidance for the present, flexibility for the

    future Considerations: Efficacy, toxicity, cost Qualities: Comprehensive, granular, dynamic Off pathway wrong

  • Stakeholders

  • Transparency and Consistency

    Getting to the table Who is involved Setting the agenda Data for consideration

    Making the meal Level of evidence Tools for considering value Quantifying the unquantifiable

    Who eats? Disseminating decisions Who is the intended target?

  • First-line Therapy in Stage IV NSCLC:Turn, Turn, Turn

  • First-line Therapy in Stage IV NSCLC:Changes

  • First-line Therapy in Stage IV NSCLC:God Only Knows

  • March of the Doublets

    Schiller JH, et al. N Engl J Med. 2002;346:92.

    Perc

    ent

    Months

    Paclitaxel/Cisplatin 7.8 10Gemcitabine/Cisplatin 8.1 13Docetaxel/Cisplatin 7.4 11Paclitaxel/Carboplatin 8.1 11

    Median Survival (mo)100

    80

    60

    40

    20

    00 5 10 15 20 25 30

    2-y Survival (%)

  • Metastatic NSCLC: First-line Therapy2002

    NSCLC

    Platinum Doublet

  • Metastatic NSCLC: First-line Therapy Today

    NSCLC

    SquamousNon-squamous

    Platinum Doublet

    Targetable Genomic Change

    No Targetable Genomic Change

    gefitinib

    afatinib

    ceritinib

    alectinib

    EGFR

    erlotinib

    ALK

    crizotinib

    ROS1

    crizotinib

    BRAF

    dabrafenib+

    trametinib

    platinum doublet +

    bevacizumab

    platinum + pemetrexed

    platinum doublet +

    necitumumab

    platinum doublet + necitumumab

    PD-L1 > 50%

    pembrolizumab

    ALK = anaplastic lymphoma kinase gene; EGFR = epidermal growth factor receptor gene.

  • Metastatic NSCLC: First-line Therapy Today

    NSCLC

    SquamousNon-squamous

    Platinum Doublet

    Targetable Genomic Change

    No Targetable Genomic Change

    gefitinib

    afatinib

    ceritinib

    alectinib

    EGFR

    erlotinib

    ALK

    crizotinib

    ROS1

    crizotinib

    BRAF

    dabrafenib+

    trametinib

    platinum + pemetrexed +

    PD-L1 > 50%

    pembrolizumab

    pembrolizumab

    ALK = anaplastic lymphoma kinase gene; EGFR = epidermal growth factor receptor gene.

  • What were you thinking?Pembrolizumab in first-line

    NSCLC with PD-L1>50%

  • Keynote 024: Study Objectives and Design

    DOR = duration of response; PD = progressive disease; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; TPS = tumor proportion score.Reck M, et al. New Engl J Med. 2016;375:1823-1833.

  • Keynote 024: Response in ITT Population

    Objective response was considered to be a confirmed complete or partial response, assessed by blinded, independent central radiologic review.Time to response and duration of response were evalueated in the patients who had an objective response.Duration of response was calculated by the Kaplan-Meier method for censored data.ITT = intent to treat; NR = Not Reached.Reck M, et al. New Engl J Med. 2016;375:1823-1833.

  • Keynote 024: PFS in ITT Population

    Reck M, et al. New Engl J Med. 2016;375:1823-1833.

  • Keynote 024: PFS in ITT Population

    Reck M, et al. New Engl J Med. 2016;375:1823-1833.

  • Keynote 024: OS in ITT Population

    Reck M, et al. New Engl J Med. 2016;375:1823-1833.

  • Keynote 024: Exposure and Safety in ITT Population

    Pembrolizumab(n=154)

    Chemotherapy(n=150)

    Exposure, months median (range) 7.0(1d 18.8 mo)

    3.5(1d 16.8 mo)

    Treatment-related AEs, n (%)Grade 3-4SeriousLed to discontinuationLed to death

    113 (73)40 (26)33 (21)11 (7)1 (< 1)

    135 (90)77 (51)31 (21)16 (11)3 (2)

    AE = adverse event.Reck M, et al. New Engl J Med. 2016;375:1823-1833.

  • Checklist

    Do we have the information we need? YesDoes it help the patient in the short term (eg, response, PFS)

    Yes

    Does it help the patient in the long term (eg, survival)

    Yes

    Is it less toxic? YesIs it less expensive? UncertainDoes it compromise future care? No

  • What were you thinking?nab-paclitaxel for first-line therapy

    of stage IV squamous-cell carcinoma

  • nab-Paclitaxel with First-line Therapy

    CONSORT: randomized 1:1 phase 3 trial of carboplatin with either paclitaxel or nab-paclitaxel

    Primary endpoint: objective response rate Overall efficacy

    Carbo + nab-paclitaxel

    Carbo + paclitaxel P-value

    N 521 531

    ORR 33% (170/521) 25% (132/531)0.005

    Response Rate Ratio 1.313(1.082 1.593)

    PFS 6.3 months 5.8 months 0.214HR 0.902 (0.767 1.060)

    OS 12.1 11.2 .271HR 0.922 (0.797 1.066)

    HR = hazard ratio.Socinski MA, et al. J Clin Oncol. 2012;30(17):2055-2062.

  • Is This Clinically Significant?Is This Cost-effective?

    Carbo + nab-paclitaxel

    Carbo + paclitaxel P-value

    Squamous41%

    (94/229)24%

    (54/221)

    .001Response Rate Ratio

    1.680 (1.271 2.221)

    Non-squamous26%

    (76/292)25%

    (78/310)

    0.808Response Rate Ratio

    1.034 (0.788 1.358)

    Socinski MA, et al. J Clin Oncol. 2012;30(17):2055-2062.

  • Comparing Costs

  • Checklist

    Do we have the information we need? YesDoes it help the patient in the short term (eg, response, PFS)

    Sort of, maybe,for SCC

    Does it help the patient in the long term (eg, survival)

    No

    Is it less toxic? MaybeIs it less expensive? NoDoes it compromise future care? No

    SCC = squamous-cell carcinoma.

  • What were you thinking?First-line therapy in ALK-

    rearranged NSCLC

  • ALK-rearranged NSCLC: Background

    2007: Soda et al publish discovery of ALKrearrangements in non-small cell lung cancer1

    2010: Kwak et al. publish results of phase I trial of crizotinib in ALK rearranged lung cancer2

    1. Soda M, et al. Nature. 2007;448(7153):561-566; 2. Kwak EL, et al. N Engl J Med. 2010;363(18):1693-1703.

  • J-ALEX: Progression-free Survival

    J-ALEX = _________.Hida T, et al. Lancet. 2017;390(10089):29-39.

  • J-ALEX: Secondary Endpoints

    Crizotinib AlectinibResponse 79% 92%Overall survival Immature, not publishedGrade 3-4 toxicity 52% 26%Drug-related dose interruption 74% 29%Drug-related discontinuation 20% 9%

    Hida T, et al. Lancet. 2017;390(10089):29-39.

  • ALEX: Progression-free Survival

    Mok TS, et al. N Engl J Med. 2017;376(7):629-640.

  • ALEX: Secondary Endpoints

    Crizotinib AlectinibGrade 3-5 toxicity 50% 41%Drug-related dose reduction 21% 16%Drug-related discontinuation 13% 11%

    Mok TS, et al. N Engl J Med. 2017;376(7):629-640.

  • ALK Inhibitors: Costs

  • Checklist

    Do we have the information we need? Yes, mostlyDoes it help the patient in the short term (eg, response, PFS)

    Yes

    Does it help the patient in the long term (eg, survival)

    No

    Is it less toxic? YesIs it less expensive? YesDoes it compromise future care? No

  • What were you thinking?Chemo + pembrolizumab in

    first-line non-squamous NSCLC

  • Keynote 021: Study Objective and Design

    AUC = Area under the curve. ECOG PS = Eastern Cooperative Oncology Group Performance Status.Langer CJ, et al. Lancet Oncol. 2016;17(11):1497-1508.

  • Keynote 021: Response and toxicity

    Chemo Chemo + pembro

    P-value

    Response Rate 29% 55% 0.0016

    Langer CJ, et al. Lancet Oncol. 2016;17(11):1497-1508.

  • Keynote 021: Progression-free Survival

    Langer CJ, et al. Lancet Oncol. 2016;17(11):1497-1508.

  • Keynote 021: Overall Survival

    Langer CJ, et al. Lancet Oncol. 2016;17(11):1497-1508.

  • Keynote 021: Toxicity

    Pembrolizumab + chemotherapy

    (n=59)

    Chemotherapy alone (n=62)

    Exposure, months median (IQR)

    8.0(4.7 to 11.2 mo)

    4.9(2.1 to 7.4 mo)

    Treatment-related AEs, n (%)Grade 34SeriousLed to discontinuation Led to death

    55 (93) 22 (37) 16 (27) 6 (10) 1 (2)

    56 (90) 14 (23) 6 (10) 8 (13) 2 (3)

    Exposure and AE summary

    IQR = interquartile range.Langer CJ, et al. Lancet Oncol. 2016;17(11):1497-1508.

  • Checklist

    Do we have the information we need? NoDoes it help the patie

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