Transcript

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 3–4SeriousLed 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 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? NoIs it less expensive? NoDoes it compromise future care? ???

What’s next?

Sorting through Immunotherapy

Targeted Testing Landscape

• Testing has largely been based on drug approvals:– EGFR - BRAF– ALK - NTRK– ROS

• Moving to next-generation sequencing

Data

Complexity of Decision-Making

Abernathy J Clin Oncol. 2010.

Factors in Decision-making

1st Line NSCLC:• Histology• Stage• Brain mets?• ECOG PS• EGFR• ALK• ROS1• PD-L1

• CrCl• LFTs• CBC• Patient concerns• Symptomatic• Trial available• Trial interest• Distance

Whom to Start at Quarterback, Fantasy Football

• Availability/byes• Opponent pass rush• Offensive line

protection• Opponent secondary• Receive matchups• Opponent offense

(high-scoring/low scoring)

• Opponent rushing defense vs offense rushing attack

• Team injuries• Opponent injuries• Past performance

against this team• Recent performance

• Home/away• Crowd noise• Distance the visiting

team has to travel• Time of game• Wind• Precipitation• Done• Confidence in the

place kicker• Coaching factors• What’s at stake

CrCL = creatinine clearance; LFTs = liver function tests; CBC = complete blood count.

Data

Patient Characteristics

DiseaseCharacteristics(incl genomics,

expression)

TreatmentDecision Decision

Capture

Outcomes

Conclusions

• Pathways in NSCLC continue to evolve as science and drug development advance

• Challenges remain regarding making meaningful comparisons, especially around value

• Pathways should play an integral part in guiding future care

Acknowledgements

Pathways TeamJoseph JacobsonCarole DalbyTeresa GreenbergJulia HallJoanna HamiltonVicky HayneLeah SteinLinda Moroni

Via OncologyKathy LokayEd RodgersStephanie SimonsLauren Bradford

DFCI Leadership SupportDorothy PuhyEric WinerCraig BunnellElizabeth LiebowPasi Jänne

Pathways ArchitectsCaroline BlockSusanna CamposMatt DavidsPeter EnzingerDavid FisherArnold FreemanEric JacobsenCaron JacobsonKerry KilbridgeAnn LaCasceEudocia LeeUrsula Matulonis

Priscilla MerriamJeff MeyerhardtOreofe OdehideClaudia Paba-PradaGuilherme RabinowitsDoug RubinsonDavid SteensmaChristopher SweeneyKatherine ThorntonMartha WadleighBrian WolpinMatt Yurgulan

PharmacyAmal ArnaoutHillary PrescottMarina KaymakcalanHoury LeblebjianAndrew SkirvinJanine NazarroChristy Harris

FinanceBelen FraileYichen Zhang

Questions?


Top Related