New Developments in Lung Cancer Therapeuticsmeccinc.com/wp-content/uploads/2017/09/REISS-Advances-in...Jonathan Riess, MD New Developments in Lung Cancer Therapeutics Relevant financial

Jonathan Riess, MDNew Developments in Lung Cancer Therapeutics

Relevant financial relationships in the past twelve months by presenter or spouse/partner.

Grant/Research Support: Merck, AstraZeneca, Millenium, NovartisConsultant: AbbVie, MedTronic, Ariad, Clovis, Celgene

The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.

Outline

• Advances in Immunotherapy (New Combinations – chemo + PD-1 in NSCLC. Ipi+Nivo SCLC)

• Advances in sequencing of new targeted therapies in EGFR and ALK NSCLC

• New Targets in SCLC (DLL2)

Progression After the Next Line of Therapy (PFS2) and Updated OS Among Patients With Advanced NSCLC and PD-L1 TPS ≥50% Enrolled in KEYNOTE-024

Julie R. Brahmer,1 Delvys Rodríguez-Abreu,2 Andrew G. Robinson,3 Rina Hui,4Tibor Csőszi,5 Andrea Fülöp,6 Maya Gottfried,7 Nir Peled,8 Ali Tafreshi,9 Sinead Cuffe,10

Mary O’Brien,11 Suman Rao,12 Katsuyuki Hotta,13 Melanie A. Leiby,14 Jessica McLean,14

Yue Shentu,14 Reshma Rangwala,14* Martin Reck15

1Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 2Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain; 3Cancer Centre of Southeastern Ontario at Kingston General Hospital, Kingston, ON, Canada; 4Westmead Hospital and the University of Sydney, Sydney, NSW, Australia; 5Jász-Nagykun-Szolnok County Hospital, Szolnok, Hungary; 6Országos Korányi TBC és Pulmonológiai Intézet, Budapest, Hungary; 7Meir Medical Center, Kfar-Saba, Israel; 8Davidoff Cancer Center, Tel Aviv University, Petah Tikva, Israel; 9Southern Medical Day Care Centre, Wollongong, NSW, Australia; 10St. James’s Hospital and Cancer Trials Ireland (formerly ICORG – All Ireland Cooperative Oncology Research Group), Dublin, Ireland; 11The Royal Marsden Hospital, Sutton, Surrey, UK; 12MedStar Franklin Square Hospital, Baltimore, MD, USA; 13Okayama University Hospital, Okayama, Japan; 14Merck & Co., Inc., Kenilworth, NJ, USA; 15Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), member of the German Center for Lung Research (DZL), Grosshansdorf, Germany. *Former employee.

KEYNOTE-024 Study Design (NCT02142738)

aOptional pemetrexed maintenance therapy for nonsquamous disease. bTo be eligible for crossover, progressive disease (PD) had to be confirmed by blinded, independent central radiology review and all safety criteria had to be met.

Key Eligibility Criteria• Untreated stage IV NSCLC• PD-L1 TPS ≥50% • ECOG PS 0-1• No activating EGFR mutation or

ALK translocation• No untreated brain metastases• No active autoimmune disease

requiring systemic therapy

Pembrolizumab 200 mg IV Q3W

(2 years)

R (1:1)N = 305

PDb Pembrolizumab 200 mg Q3W for 2 years

Platinum-Doublet Chemotherapya

(4-6 cycles)

Key End PointsPrimary: PFS (RECIST v1.1, blinded independent central review)Secondary: OS, ORR, safetyExploratory: DOR, PFS2

0 3 6 9 1 2 1 5 1 8 2 1 2 40

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

PF

S2

, %

N o . a t r is k

1 5 4 1 3 4 1 1 2 96 90 71 40 16 31 5 1 1 2 1 99 64 56 36 18 6 1

Kaplan-Meier Estimate of PFS2

aNominal P value.Assessed per RECIST v1.1 by investigator review.

Data cutoff: Jan 5, 2017.

Events, n

HR (95% CI)

Pembrolizumab 74 0.54

(0.40-0.72)

P < 0.001aChemotherapy 110

59.7%38.5%

51.0%24.6%

Median (95% CI)18.3 mo (12.7-NE)8.4 mo (6.8-9.8)

Kaplan-Meier Estimate of OS: Updated Analysis

0 3 6 9 12 15 18 21 240

102030405060708090

100

Time, months

OS

, %

No. at risk154 136 121 112 106 88 57 20 4151 123 107 88 79 64 35 15 4

aNominal P value.Data cutoff: Jan 5, 2017.

Events, n

HR (95% CI)

Pembrolizumab 63 0.63

(0.46-0.88)

P = 0.003aChemotherapy 84

70.3%54.8%

61.2%43.0%

Median (95% CI)NR (19.4 mo-NE)14.5 mo (9.8-19.6)

Median fup 19.1 months

Concurrent Chemotherapy and Pembrolizumab in Non-Squamous NSCLC

Presented by: Jonathan Riess, MD MS

ORR 55% vs. 29%, p=0.0016

PFS: HR 0.53, p=0.01CJ Langer et al. Lancet Oncol 2016.

Carboplatin Pemetrexed Pembrolizumab FDA accelerated approval for firstline treatment of non-squamous NSCLC

regardless of PD-L1 status based on phase 2 KEYNOTE 021 data on 123 patients

Alectinib vs crizotinib in treatment-naïve advanced ALK+ NSCLC: primary results of the global phase III ALEX study (LBA9008)

Alice Shaw1, Solange Peters2, Tony Mok3, Shirish M. Gadgeel4, Jin Seok Ahn5, Sai-Hong Ignatius Ou6, Maurice Perol7, Rafal Dziadziuszko8, Dong-Wan Kim9, Rafael Rosell10, Ali Zeaiter11, Ting Liu11, Sophie Golding11, Bogdana Balas11, Johannes Noe11, Peter N. Morcos12, and D. Ross Camidge13 on behalf of the ALEX investigators

1. Massachusetts General Hospital, Boston, MA, USA; 2. Lausanne University Hospital, Switzerland; 3. Chinese University of Hong Kong, Hong Kong; 4. Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA; 5. Sungkyunkwan University School of Medicine, Seoul, South Korea; 6.Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Orange, CA, USA; 7. Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France; 8. Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; 9. Seoul National University Hospital, Seoul, South Korea; 10. Catalan Institute of Oncology, Barcelona, Spain; 11. F. Hoffmann-La Roche Ltd, Basel, Switzerland; 12. Roche Innovation Center, New York, USA; 13. University of Colorado, Denver, CO, USA

http://tago.ca/Lfq

Study design

KEY ELIGIBILITY● Advanced or metastatic

ALK+ NSCLC● ALK+ by central IHC

testing● Treatment-naïve● ECOG PS 0−2● Measurable disease● Asymptomatic brain

metastases allowed

Alectinib600 mg BID PO

Crizotinib250 mg BID PO

ENDPOINTS● Primary

– PFS (RECIST 1.1), by investigator review

● Secondary– PFS by IRC– Time to CNS progression– ORR, DOR– OS– Safety and tolerability– Patient-reported

outcomes

RANDOMIZE

NO CROSSOVERper protocol

Presented by: Alice T. Shaw

ALK, anaplastic lymphoma kinase; IHC, immunohistochemistry; NSCLC, non-small-cell lung cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; PO, by mouth; PFS, progression-free survival; IRC, independent review committee; CNS, central nervous system; ORR, objective response rate; DOR, duration of response; OS, overall survival

Stratification factors: • ECOG PS (0/1 vs 2) • Race (Asian vs non-Asian) • Brain metastases (present vs absent)

N=286

Baseline CNS disease


Crizotinib(N=151)

Alectinib(N=152)

CNS metastases by IRC (%)

Present 58 (38) 64 (42)

Absent 93 (62) 88 (58)

CNS metastases treatment (%)

n 58 64

None 36 (62) 37 (58)

Whole brain RT

16 (28) 17 (27)

Radiosurgery 4 (7) 5 (8)

Other* 1 (2) 4 (6)

Brain surgery 1 (2) 1 (2)*1 patient in the alectinib arm received both radiosurgery and whole brain radiotherapy; 1 patient in the crizotinib arm and 3 patients in the alectinib arm had brain surgery combined with radiotherapy

CNS, central nervous system; IRC, Independent Review Committee, RT, radiotherapy

Primary endpoint: PFS, investigator-assessed


Crizotinib

(N=151)

Alectinib

(N=152)

Patients with events, n (%)

102 (68) 62 (41)

Median PFS, months (95% CI)

11.1(9.1–13.1)

NR(17.7–NR)

HR (95% CI)P-value (log-rank test)

0.47 (0.34–0.65)P<0.00010

20

40

60Alectinib

100

1 3 6 9 12 15 18 21 24 27 30

Crizotinib

151 132 104 84 65 46 35 16 5

152 135 113 109 97 81 67 35 15 3

Crizotinib

Alectinib

No. at Risk

80

Prog

ress

ion-

free

Sur

viva

l (%

)

Day

11.1 months

Months

NR

Secondary endpoint: Time to CNS progression (by IRC, ITT)


Cumulative incidence of CNS progression

0

10

20

30

60

1 6 12 18 24 30

40

50

Crizotinib12 month CIR:41.4% (95% CI, 33.2–49.4)

Alectinib12 month CIR:9.4% (95% CI, 5.4–14.7)

Months

Cum

ulat

ive

Inci

denc

e (%

)

• A competing risk analysis with CNS progression, non-CNS progression and death as competing events was conducted

• For each patient, the first event of CNS progression, non-CNS progression or death was counted

Crizotinib(N=151)

Alectinib(N=152)


68 (45) 18 (12)

Cause-specific HR (95% CI)P-value (log-rank test)

0.16 (0.10–0.28)P<0.0001

Objective response rate*


Crizotinib(N=151)

Alectinib(N=152)

Responders, n (%) 114 (76) 126 (83)(95% CI) (68–82)

P=0.09(76–89)

Complete response, n (%)

2 (1) 6 (4)

Partial response, n (%) 112 (74) 120 (79)Stable disease, n (%) 24 (16) 9 (6)Median DOR (months) 11.1 NR

(95% CI) (7.9–13.0)HR=0.3

6

(NR)*Investigator assessment

Adverse events, ≥10% between treatment armsCrizotinib (N=151) Alectinib (N=152)

N (%) Any grade Grade 3–5

Any grade Grade 3–5

Nausea 72 (48) 5 (3) 21 (14) 1 (1)Diarrhea 68 (45) 3 (2) 18 (12) 0Vomiting 58 (38) 5 (3) 11 (7) 0Peripheral edema 42 (28) 1 (1) 26 (17) 0Dysgeusia 29 (19) 0 4 (3) 0ALT increased 45 (30) 22 (15) 23 (15) 7 (5)AST increased 37 (25) 16 (11) 21 (14) 8 (5)Visual impairment 18 (12) 0 2 (1) 0Blood bilirubin increased

2 (1) 0 23 (15) 3 (2)

Myalgia 3 (2) 0 24 (16) 0Anemia 7 (5) 1 (1) 30 (20) 7 (5)Weight increased 0 0 15 (10) 1 (1)


AE, adverse event; ALT, alanine aminotransferase; AST, aspartate transaminase

Secondary endpoint: OS


0

20

40

60

100

1 3 6 9 12 15 18 21 24 27 30

Months

80

Day

151 141 127 115 103 95 73 33 13

152 142 131 127 119 107 87 51 24 5

Crizotinib

Alectinib

No. at Risk

1

Alectinib

Crizotinib

Ove

rall

Surv

ival

Crizotinib

(N=151)

Alectinib

(N=152)


40 (27) 35 (23)

Median OS, months (95% CI)

NR(NR)

NR(NR)

HR (95% CI)P-value (log-rank test)

0.76 (0.48–1.20)

P=0.24

Shaw et al, ALEX: PFS underpinned by CNS activity

Presented by: Sanjay Popat @drsanjaypopat

HR=0.50 (95% CI:0.36–0.70), P<0.0001Median PFS >2 years

~4 fold reduction

~month 4

J-ALEX vs ALEX vs ASCEND 4: efficacy


Trial J-ALEX ALEX J-ALEX ALEX ASCEND4

Drug crizotinib

crizotinib

alectinib alectinib ceritinib

n 104 151 103 152 189

Median PFS 10.2 10.4 NR (>21) 25.7 16.6

PFS HR (95% CI)

0.34**(0.17-0.71)

0.50**(0.36-0.70)

0.55*(0.42-0.73)

ORR (%) 79 76 92 83 73

Median PFSBM+

10.2 7 NR (>21) NR (>27) 10.7

Median PFS BM-

10.0 15 20.3 NR (>27) 26.3

Intracranial - 50 - 81 73

Shaw ASCO (2017); Hida Lancet (2017); Kim WCLC (2016) #5597; Soria Lancet (2017); NR, not reached; * vs chemotherapy; ** vs crizotinib

ALEX: Summary and Conclusions (My Take)

Presented by: Jonathan Riess, MD MS

• Alectinib is the new standard for 1st line ALK TKI• OS is immature but no current signal of superiority with

alectinib• Magnitude of PFS benefit is compelling (HR=0.47)

– PD on crizotinib is salvageable– Neuroprotective– CNS for failure is major issue with crizotinib (41% at 1yr)

EGFR TKIs vs Chemotherapy in EGFR-Mutated NSCLC

1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Mitsudomi T, et al. ASCO 2012. Abstract 7521. 4. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 5. Zhang C, et al. ASCO 2012. Abstract 7520. 6. Rosell R, et al. Lancet Oncol. 2012;13:239-246. 7. Yang J C-H, et al. ASCO 2012. Abstract LBA 7500.

Study Treatment RR Median PFS (mo)

Median OS

NEJ002[1]

N=230Gefitinib vs carboplatin/paclitaxel

74 v 31% 10.8 vs 5.4(P < .001)

30.5 vs 23.6HR = 0.89

WJOTG[2,3]

N=177Gefitinib vs

CDDP/docetaxel

62 v 32% 9.2 vs 6.3(P < .0001)

36 vs 39HR = 1.25

OPTIMAL[4,5]

N=165Erlotinib vscarboplatin/gemcitabine

83 v 36% 13.1 vs 4.6(P < .0001)

30.4 vs 31.5HR = 1.065

EURTAC[6]

N=174Erlotinib vs

platinum-based chemotherapy

58 v 15% 9.7 vs 5.2(P < .0001)

19.3 vs 19.5HR = 0.93

LUX-Lung 3[7]

N=345 Afatinib vsCDDP/Pem

61 v 22% 11.1 vs 6.9(P < .0004)

28.2 vs 28.2HR = 0.88

LUX-Lung-6N=364

Afatinib vs CDDP/Gem

67 v 23% 11.0 v. 5.6HR = 0.28

23.1 vs 23.5HR = 0.93

• Gefitinib, Erlotinib & Afatinib all superior to Platinum chemotherapy for RR & PFS• No improvement in OS in these randomized trials

ARCHER 1050: Study Design

• Phase III randomized open-label study to evaluate dacomitinib as an alternative first-line treatment for patients with advanced NSCLC with an EGFR-activating mutation

ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT01774721

● Advanced NSCLC with EGFR-activating mutation(s)

● No prior systemic treatment of advanced NSCLC

● No CNS metastasis● No prior EGFR TKI or other TKI● ECOG PS 0,1

N=452

Secondary endpointsPFS (investigator assessed),

ORR, DOR,TTF, OS, Safety, PROs

Primary endpoint PFS by blinded independent

review (IR)• ≥256 PFS events• PFS HR≤0.667 (50%↑)• 90% power• 1-sided α =0.025• mPFS: 14.3 vs 9.5 months

R1:1

Stratification factorsRace (inc. Asian vs non-

Asian) EGFR mutation type

(exon 19 vs 21)

Dacomitinib 45 mg PO QD

(N=227)

Gefitinib250 mg PO QD

(N=225)

4Presented by: Tony Mok, MD

PFS: Blinded Independent Review (ITT population)

MonthsNo. at risk

Dacomitinib

Gefitinib

227

225

154

155

106

69

73

34

20

7

6

1

0

0

0

0

1.0

0.8

0.6

Prob

abilit

y of

PFS

0.4

0.2

0.00 6 12 18 24 30 36 42

Censored

PFS rate 30.6% vs 9.6%

7

Daco (N=227)

Gef(N=225)

Number of Events, n (%)

136(59.9%)

179(79.6%)

Median PFS (95% CI)

14.7 (11.1, 16.6)

9.2 (9.1, 11.0)

HR (95% CI)0.59 (0.47–0.74)

P<0.0001

Presented by: Tony Mok, MD

Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD) Indeterminate (IND)

ORR: Tumor change per blinded IRC review

Shown are best responses in patients treated with dacomitinib or gefitinib. Each bar represents an individual patient’s maximum reduction in target lesion size.

Max

imum

cha

nge

from

bas

elin

e(%

)

50

40

30

20

10

0

-10

-30

-40

-50

-60

-70

-80

-90

-100

-20

Dacomitinib 50

40

30

20

10

0

-10

-30

-40

-50

-60

-70

-80

-90

-100

-20

Gefitinib

Presented by: Tony Mok, MD 12

Adverse Events from Any Cause

Dacomitinib (N = 227) Gefitinib (N = 224)

Adverse event Any Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any

Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Number of patients (percent)

Diarrhea 198 (87.2)

113(49.8) 65 (28.6) 19 (8.4) 0 1 (0.4) 125

(55.8)103

(46.0) 20 (8.9) 2 (0.9) 0 0

Paronychia 140 (61.7) 46 (20.3) 77 (33.9) 17 (7.5) 0 0 45 (20.1) 30 (13.4) 12 (5.4) 3 (1.3) 0 0

Dermatitis acneiform

111 (48.9) 37 (16.3) 43 (18.9) 31 (13.7) 0 0 64 (28.6) 43 (19.2) 21 (9.4) 0 0 0

Stomatitis 99 (43.6) 51 (22.5) 40 (17.6) 8 (3.5) 0 0 40 (17.9) 33 (14.7) 6 (2.7) 1 (0.4) 0 0

Decreased appetite 70 (30.8) 40 (17.6) 23 (10.1) 7 (3.1) 0 0 55 (24.6) 48 (21.4) 6 (2.7) 1 (0.4) 0 0

Dry skin 63 (27.8) 42 (18.5) 18 (7.9) 3 (1.3) 0 0 38 (17.0) 35 (15.6) 3 (1.3) 0 0 0

Weight decreased 58 (25.6) 31 (13.7) 22 (9.7) 5 (2.2) 0 0 37 (16.5) 22 (9.8) 14 (6.3) 1 (0.4) 0 0

Alopecia 53 (23.3) 41 (18.1) 11 (4.8) 1 (0.4) 0 0 28 (12.5) 26 (11.6) 2 (0.9) 0 0 0

Cough 48 (21.1) 39 (17.2) 9 (4.0) 0 0 0 42 (18.8) 36 (16.1) 5 (2.2) 1 (0.4) 0 0

Pruritus 45 (19.8) 27 (11.9) 17 (7.5) 1 (0.4) 0 0 31 (13.8) 24 (10.7) 4 (1.8) 3 (1.3) 0 0

ALT increased 44 (19.4) 37 (16.3) 5 (2.2) 2 (0.9) 0 0 88 (39.3) 45 (20.1) 24 (10.7) 19 (8.5) 0 0

Adverse events occurring in at least 15% of the patients in either study group in the safety population. Events are listed in descending order of frequency in the dacomitinib group.

13Presented by: Tony Mok, MD

LUX-Lung 7: Phase 2b trial


open label controlled brain mets

Park Lancet Oncol (2016)

12 months

LUX7 vs ARCHER 1050: efficacy & dosing


Trial LUX7 1050 LUX7 1050

Drug gefitinib gefitinib

afatinib dacomitinib

n 159 225 160 227

Efficacy

Median PFS 10.9 9.2 11.0 14.7

PFS HR (95%CI)

- - 0.73 (0.57-0.95)

0.59 (0.47-0.74)

24 month PFS

8% 10% 18% 31%

Dosing

Dose modification

2% 8% 42% 66%

Janjigian et al., Cancer Discov. 2014;4:1036

S1403: A Randomized Phase 2/3 Trial of Afatinib + Cetuximab Versus Afatinib Alone in Treatment-Naïve Pts With Advanced, EGFR Mutation + NSCLC

Dual Inhibition: Afatinib + Cetuximab

Mechanisms of Acquired Resistance to EGFR TKIs in EGFR-mutated Lung Cancers

● At the time of acquired resistance, T790M is found in over 50% of repeat biopsies1

● T790M may not always be the cause of clinical resistance, even when present

● Several bypass mechanisms of resistance, including MET or HER2 amplification, or PIK3CA or BRAF mutation, have now been identified

● SCLC transformation can also occur, but is uncommon-rare

Camidge et al., Nature Rev Clin Oncol, 2014

AURA3 study designKey eligibility criteria• ≥18 years (≥20 years in Japan)

• Locally advanced or metastatic NSCLC

• Evidence of disease progression following first-line EGFR-TKI therapy

• Documented EGFRm and central confirmation of tumour EGFR T790M mutation from a tissue biopsy taken after disease progression on first-line EGFR-TKI treatment

• WHO performance status of 0 or 1

• No more than one prior line of treatment for advanced NSCLC

• No prior neo-adjuvant or adjuvant chemotherapy treatment within 6 months prior to starting first EGFR-TKI treatment

• Stable* asymptomatic CNS metastases allowed

R 2:1

Osimertinib (n=279)80 mg orally

QD

Platinum-pemetrexed (n=140)

Q3W for up to 6 cycles+ optional

maintenance pemetrexed#

EndpointsPrimary:• PFS by investigator assessment

(RECISTv1.1)Secondary and exploratory:• Overall survival • Objective response rate • Duration of response • Disease control rate • Tumour shrinkage• BICR-assessed PFS• Patient reported outcomes• Safety and tolerability

Papadimitrakopoulou et al: ESMO 2016

• Analysis of PFS by BICR was consistent with the investigator-based analysis: HR 0.28 (95% CI 0.20, 0.38), p<0.001; median PFS 11.0 vs 4.2 months.

Population: intent-to-treatProgression-free survival defined as time from randomisation until date of objective disease progression or death.Progression included deaths in the absence of RECIST progression.

Tick marks indicate censored data; CI, confidence interval

AURA3 primary endpoint: PFS by investigator assessment

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18

Prob

abili

ty o

fpr

ogre

ssio

n-fr

ee su

rviv

al

No. at riskOsimertinib

Platinum-pemetrexed

Months

279140

24093

16244

8817

507

131

00

Median PFS, months (95% CI)

HR (95% CI)

10.1 (8.3, 12.3)0.30 (0.23, 0.41)

p<0.0014.4 (4.2, 5.6)

Osimertinib

Platinum-pemetrexed

Papadimitrakopoulou et al: ESMO 2016

Osimertinib PFS is longest in those patients with T790M positive cancers

Tumour T790M positive predicts for a prolonged median PFS of 9.7 months, longer than seen in tumour T790M negative cases

(p<0.001)

100

24

80

60

40

20

00 3 6 9 12 15 18 21

All patients with tumour T790M results

Prob

abili

ty o

f pro

gres

sion

-free

surv

ival

Tumour T790M negative (n=58)Tumour T790M positive (n=179)

Median PFS (95% CIs)

Tumour T790M positive 9.7 (8.3, 12.5)Tumour T790M negative 3.4 (2.1, 4.3)

Log-rank test p<0.001

Time from first dose (months)

Oxnard et al. ELCC 2016

FLAURA: Phase 3, Double-Blind, Randomized Study of Osimertinib as First-line Therapy

Osimertinib(80 mg orally once daily)

Erlotinib 150 mg once daily†

ORGefitinib 250 mg once daily†

Primary endpoint:• PFSSecondary endpoints:• ORR• PFS in T790M(+/–)

patients• OS• PROs

Patients• Biopsy-confirmed,*

EGFRm NSCLC• Treatment-naïve

for advanced NSCLC

Key inclusion criteria:

• Age ≥18 years

• Locally advanced or metastatic NSCLC

• No prior therapy for advanced diseaseǂ

• Patients must have EGFR TKI-sensitizing mutation (ex19del or L858R)

• Mandatory tumor sample of sufficient quantity to allow central analysis of EGFR mutation status

• Enrollment is ongoing

• Estimated primary completion May 2017

A Phase I Trial of AZD9291 and Necitumumab in EGFR Mutant NSCLC with Previous EGFR-TKI

Resistance

3+3 dose escalation of AZD9291 and

Necitumumab in Advanced EGFR

Mutant NSCLC with Previous EGFR-TKI

Resistance (1st-3rd gen)

Dose Expansion in 12 evaluable EGFR T790M negative patients with EGFR-TKI as last previous treatment (afatinib, gefitinib,

erlotinib).

Primary Endpoint: Safety and TolerabilityMain Secondary Endpoint: ORR is T790M negative population(3≥12 responses)

PI: JW Riess (UCD)Co-PI David Gandara (UCD)Statistician: Susan Groshen (USC)

MTD

Creation of EGFR-TKI resistant PDXSingle Cell NGS for Intratumoral Heterogeneity

Dose Escalation of Osimertinib and Necitumumab in Advanced EGFR

Mutant NSCLC with Previous EGFR-TKI Resistance (1st-3rd

gen)

Cohort A: T790M negative, PD on afatinib, gefitinib, erlotinib as last

treatment

MTD

Cohort D: EGFR Exon 20 Insertion NSCLC with PD on platinum based

chemotherapy

Cohort B: EGFR T790M negative, PD on osimertinib or other 3rd gen EGFR-

TKI

Cohort C: EGFR T790M positive, PD on osimertinib or other 3rd gen EGFR-

TKI

Vanderbilt SC16LD6.5 Trial Case Western0

50

100

150

200

250

300C

ell

ula

r M

em

bra

ne

H-S

co

re

n = 50Courtesy of A. Dowlati

n = 106 n = 22

VANDYTMA

(Naïve)

SC16LD6.5TRIAL

(Naïve)

CASE WSTTMA

C/E exposed

60% 70% 75%

22% 12% 10%

18% 18% 15%

High Expression

(DLL3+)

MediumExpression

LowExpression

Courtesy of P. Massion

Rudin Oral 10.01

Nivolumab ± Ipilimumab in Advanced Small Cell Lung Cancer: First Report of a Randomized Cohort From

CheckMate 032

Matthew D. Hellmann,1 Patrick A. Ott,2 Jon Zugazagoitia,3 Neal Ready,4 Christine L. Hann,5 Filippo de Braud,6 Scott Antonia,7 Paolo A. Ascierto,8 Victor Moreno,9 Akin Atmaca,10

Stefania Salvagni,11 Matthew Taylor,12 Asim Amin,13 D. Ross Camidge,14 Leora Horn,15

Emiliano Calvo,16 Weiguo Cai,17 Justin Fairchild,17 Margaret Callahan,1 David Spigel18

1Memorial Sloan Kettering Cancer Center, New York, NY, USA USA; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3Hospital Universitario12 de Octubre, Madrid, Spain; 4Duke University Medical Center, Durham, NC, USA; 5The Sidney Kimmel Comprehensive Cancer Center at

Johns Hopkins University, Baltimore, MD, USA; 6Fondazione IRCCS Instituto Nazionale dei Tumori Milano, Milan, Italy; 7H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; 8Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; 9START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain; 10Krankenhaus Nordwest GmbH Institut für Klinisch-Onkologische Forschung, Frankfurt am Main,

Germany; 11Policlinico Sant’Orsola – Malpighi University Hospital, Bologna, Italy; 12Oregon Health & Science University, Portland, OR, USA;13Levine Cancer Institute, Carolinas Medical Center, Charlotte, NC, USA; 14University of Colorado Cancer Center, Aurora, CO, USA; 15Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 16START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain;

17Bristol-Myers Squibb, Princeton, NJ, USA; 18Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA

CheckMate 032: Nivolumab ± Ipilimumab in Advanced Small Cell Lung Cancer (SCLC): Background

• Patients with recurrent SCLC have limited treatment options and poor survival1–6

• CheckMate 032, a phase I/II trial, is evaluating nivolumab ± ipilimumab in recurrent SCLC and other tumor types7

• Initial results showed durable responses and encouraging survival7,8

– Data supported the inclusion of nivolumab ± ipilimumab in NCCN Guidelines9

• A randomized cohort was added to further evaluate nivolumab ± ipilimumab in patients with SCLC whose disease progressed after platinum-based therapy

NCCN = National Comprehensive Cancer Network 39

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC Phase I/II CheckMate 032 Study Design – Non-Randomized Cohort

• Update includes response per blinded independent central review (BICR)

– Additional follow-up of ~6 months from prior disclosure8

aMedian follow-up 23.3 mo; bMedian follow-up 28.6 moFollow-up was calculated as time from first dose to database lock 40

Primary objective: ORR per RECIST v1.1

NON-RANDOMIZED COHORT RANDOMIZED COHORT

Randomize 3:2

Database lock: March 30, 2017

Nivolumab 3 mg/kg IV Q2W

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV

Q3W for 4 cycles Nivolumab 3 mg/kg IV

Q2W(n = 147)


Q3W for 4 cycles (n = 95)

Until disease progression or

unacceptable toxicity

Nivolumab 3mg/kg IV Q2W until disease

progression or unacceptable toxicity





• Patients with SCLC • ≥1 prior platinum-containing regimen (1 or 2 prior therapies for randomized cohort) • PD-L1 unselected

Primary objective: ORR per RECIST v1.1

(n = 98)a (n = 61)b

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC Summary of Response per BICR – Non-Randomized Cohort

PD-L1 expression

ORR, % (n/N)Nivolumab (n =

98)Nivolumab + Ipilimumab

(n = 61) Less than 1%

14 (9/64) 32 (10/31)

1% or more 9 (1/11) 10 (1/10)

ORR by tumor PD-L1 expression

≥1%

<1%

Tumor PD-L1 expression in non-randomized cohort (n = 159)b

Nivolumab (n = 98)

Nivolumab + Ipilimumab (n = 61)

ORR, % (95% CI) 11 (6, 19) 23 (13, 36)

Median time to response, mo(range)

1.4 (1.1–4.1) 2.0 (1.0–4.1)

Median DOR, mo (range) 17.9 (2.8–34.6+) 14.2 (1.5–26.5+)

Patients with ongoing responses at 2 yr,a %

45 36

Summary of response

18%

82%

DOR = duration of response; ipi = ipilimumab; nivo = nivolumab; aPercentage of responders (nivo, n = 11; nivo + ipi, n = 14)bPercentage of patients with quantifiable PD-L1 expression; PD-L1 expression was not evaluable/missing in 43 patients (27%) 41

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC OS – Non-Randomized Cohort

Events/number

at risk

Median OS, months(95% CI)

Minimumfollow-up,a

months

Nivolumab 82/98 4.1 (3.0, 6.8) 19.6

Nivolumab + Ipilimumab 47/61 7.8 (3.6,

14.2) 20.2

1-yr OS = 40%

1-yr OS = 27%

2-yr OS = 14%

Time (months)

OS

(%)

100

90

80

70

60

50

40

30

10

0

20

Nivolumab

Number of patients at risk

46771217212635395698

137141619212428334361Nivolumab + Ipilimumab

330 30272421181512963 36 39

04

01

2-yr OS = 26%

OS = overall survival; aBetween first dose and database lock; follow-up shorter for patients who died prior to database lock 42

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC Phase I/II CheckMate 032 Study Design – Randomized Cohort

• Interim descriptive analysis of the randomized cohort– Median follow-up: nivo, 10.8 mo; nivo + ipi, 11.2 mo

aMedian follow-up 23.3 mo; bMedian follow-up 28.6 moFollow-up was calculated as time from first dose to database lock 43

NON-RANDOMIZED COHORT RANDOMIZED COHORT

Randomize 3:2

Database lock: March 30, 2017


(n = 98)a


Q3W for 4 cycles (n = 61)b


(n = 147)


Q3W for 4 cycles (n = 95)









• Patients with SCLC • ≥1 prior platinum-containing regimen (1 or 2 prior therapies for randomized cohort) • PD-L1 unselected

Primary objective: ORR per RECIST v1.1 Primary objective: ORR per RECIST v1.1

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLCBaseline Patient Characteristics – Randomized Cohort

Nivolumab(n = 147)

Nivolumab + Ipilimumab(n = 95)

Median age, yr (range)≥65 yr, %

63.0 (29–83)44

65.0 (41–91)51

Male, % 59 63Prior treatment regimens, %12–3

6733

6733

Platinum sensitivity, %Sensitive ResistantUnknown/not reported

50491

42571

Smoking status, %Current/former smoker Never-smokerUnknown

9271

9541

ECOG PS, %01Not reported

33670

28711

44

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLCSummary of Response per BICR

OR

R (

%)

Non-randomized cohort

98 61n

Randomized cohort

147 95

12 11

21 23

0

5

10

15

20

25

30

35

40

Nivo non-randomized cohort

Nivo + ipi non-randomized cohort

Nivo randomized cohort

Nivo + ipi randomized cohort

Error bars indicate 95% CIs; 95% CIs are as follows – nivo (randomized): 7, 18; nivo + ipi (randomized): 13, 31; nivo (non-randomized): 6, 19; nivo + ipi (non-randomized): 13, 36

• Complete responses were achieved in 2 patients in the randomized cohort (nivolumab, n = 1; nivolumab + ipilimumab, n = 1)• Median time to response in the randomized cohort was comparable to that in the non-randomized cohort

– Nivolumab, 1.5 mo; nivolumab + ipilimumab, 1.4 mo

45

65 596472

0

10

20

30

40

50

60

70

80

90

182730

36

0

10

20

30

40

50

60

70

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC 3-month PFSa and OS Rates

• Minimum follow-up time was 12 weeks at the time of database lock

Nivo randomized cohort Nivo + ipi randomized cohort Nivo non-randomized cohort Nivo + ipi non-randomized cohort

PFS = progression-free survival; Error bars indicate 95% CIs; aPer BICR

PFS

(%)

OS

(%)

n

Randomized cohort

147 95


98 61 n

Randomized cohort

147 95


98 61

46

3-month PFS Rate 3-month OS Rate

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLCORR by Subgroups – Pooled Cohorts

NivolumabNivolumab + Ipilimumab

nORR,

%95% CI n

ORR, %

95% CI

Overall population 245

11 8, 16 156

22 16, 29

Line of therapySecond-lineThird-line and beyond

137108

1211

7, 186, 19

9858

1926

12, 2915, 39

Platinum sensitivity (all treated patients)a

Platinum-sensitivePlatinum-resistant

133

110

1310

8, 205, 17

8565

2615

17, 368, 26

aPlatinum sensitivity was unknown for 2 patients in the nivo arm and 6 patients in the nivo + ipi arm 47

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLCSummary of Safety – Pooled Cohorts

• Median time to resolution of grade 3–4 select TRAEs ranged from 1.8 wk (gastrointestinal events) to 16.3 wk (hepatic events) in the nivolumab + ipilimumab arm and from 3.4 wk (pulmonary events) to not reached (renal and hepatic events) in the nivolumab arm

• There were a total of 5 treatment-related deathsb

– 4 with nivolumab + ipilimumab (due to myasthenia gravis, pneumonitis, seizures/encephalitis, and autoimmune hepatitis)c

– 1 with nivolumab (due to pneumonitis)

Nivolumab (n = 245)Nivolumab + Ipilimumab (n

= 156)Any grade,

%Grade 3–4, % Any grade,

%Grade 3–4, %

Any TRAEs 55 12 73 37TRAEs leading to discontinuation 3 2 13 10

Select TRAEs by categorySkin 16 <1 36 6

Endocrine 8 0 21 3

Hepatic 6 2 12 6

Gastrointestinal 5 0 24 8

Hypersensitivity/infusion reaction 5 0 1 0

Pulmonary 3 2 4 3

Renal 1 <1 1 0

Grade 3–4 select TRAEs that resolved, %a 45 78

TRAE = treatment-related adverse event; aPercentage of total number of grade 3-4 select TRAEs across categories (nivo + ipi, n = 40; nivo, n = 11); bIn addition, there was one death in the nivo + ipi arm for which both disease progression and colitis were felt to be contributing factors; cA previously reported death due to renal failure was subsequently determined to not be related to treatment

48

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLCSummary of Safety – Pooled Cohorts

• Median time to resolution of grade 3–4 select TRAEs ranged from 1.8 wk (gastrointestinal events) to 16.3 wk (hepatic events) in the nivolumab + ipilimumab arm and from 3.4 wk (pulmonary events) to not reached (renal and hepatic events) in the nivolumab arm

• There were a total of 5 treatment-related deathsb

– 4 with nivolumab + ipilimumab (due to myasthenia gravis, pneumonitis, seizures/encephalitis, and autoimmune hepatitis)c

– 1 with nivolumab (due to pneumonitis)

Nivolumab (n = 245)Nivolumab + Ipilimumab (n

= 156)Any grade,

%Grade 3–4, % Any grade,

%Grade 3–4, %

Any TRAEs 55 12 73 37TRAEs leading to discontinuation 3 2 13 10

Select TRAEs by categorySkin 16 <1 36 6

Endocrine 8 0 21 3

Hepatic 6 2 12 6

Gastrointestinal 5 0 24 8

Hypersensitivity/infusion reaction 5 0 1 0

Pulmonary 3 2 4 3

Renal 1 <1 1 0

Grade 3–4 select TRAEs that resolved, %a 45 78

TRAE = treatment-related adverse event; aPercentage of total number of grade 3-4 select TRAEs across categories (nivo + ipi, n = 40; nivo, n = 11); bIn addition, there was one death in the nivo + ipi arm for which both disease progression and colitis were felt to be contributing factors; cA previously reported death due to renal failure was subsequently determined to not be related to treatment

49

CheckMate 451: study design10

• Currently enrolling patients

• Primary outcome measures: – OS, PFS

• Secondary outcome measures: – OS and PFS descriptive analyses: nivolumab vs nivolumab +

ipilimumab

CheckMate 331: study design11

• Primary outcome measures: – OS

• Secondary outcome measures: – PFS, ORR

Key eligibility criteria• ED-SCLC• Ongoing SD/PR/CR after

4 cycles of 1L PLT-CT• No symptomatic

CNS metastases• Toxicities from prior

therapy resolved to grade ≤1

• ECOG PS ≤1

Nivolumab

Placebo

Nivolumab+

Ipilimumab

Key eligibility criteria• SCLC• Recurrence/PD after 1L

PLT-CT or CRT (≥4 cycles)

• ECOG PS ≤1• No symptomatic CNS

metastases• No prior therapy

with anti–CTLA-4, anti–CD137, anti–PD-1/PD-L1/PD-L2

Topotecan or Amrubicina

Ran

dom

ize

1:1:

1

Ran

dom

ize

1:1

1L = first-line; CT = chemotherapy; CRT = chemoradiation therapy; CTLA-4 = cytotoxic T lymphocyte antigen-4; PD-1 = programmed-death 1; PD-L2 = PD ligand 2PLT = platinum-based; aWhere locally approved

N = 810 N = 480

Nivolumab

50

Ongoing Phase 3 Studies With Nivolumab ± Ipilimumab in SCLC“Switch maintenance” “Second line”

Summary

51

• In a randomized cohort, efficacy was consistent with the non-randomized cohort– There is indeed a separation of responses, but follow up very short– These data support use off-label in SCLC in second or third line treatment (was

already in NCCN) but randomized data are still sparse– Unclear whether nivo alone, or combo therapy, is better on “average” than single

agent chemo choices in 2nd line – Note the nivo/ipi dosing – nivo 1 mg/kg Q2W, ipi 3 mg/kg Q3W – consider reverse

dose levels and ipi Q6W (or less)

• Responses observed regardless of platinum sensitivity, line of therapy, PD-L1 status– Ideally we would be able to identify a predictive biomarker of response to avoid

exposing non-responders to toxicity (and depriving them of second line chemo)

• Grade 3/4 TRAEs and deaths were more common with nivolumab + ipilimumab than with nivolumab– Consistent with prior studies in melanoma and NSCLC, but second line SCLC

patients can’t tolerate much toxicity, and the tox analysis was pooled

– BEWARE of irAEs in SCLC!!!

Documents

New Developments in Lung Cancer Therapeuticsmeccinc.com/wp-content/uploads/2017/09/REISS-Advances-in...Jonathan Riess, MD New Developments in Lung Cancer Therapeutics Relevant financial