New Developments in Lung Cancer...
Transcript of New Developments in Lung Cancer...
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
Presented by: Alice T. Shaw
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
Presented by: Alice T. Shaw
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)
Presented by: Alice T. Shaw
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)
Patients with events, n (%)
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*
Presented by: Alice T. Shaw
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)
Presented by: Alice T. Shaw
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate transaminase
Secondary endpoint: OS
Presented by: Alice T. Shaw
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)
Patients with events, n (%)
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
Presented by: Sanjay Popat @drsanjaypopat
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
Presented by: Sanjay Popat @drsanjaypopat
open label controlled brain mets
Park Lancet Oncol (2016)
12 months
LUX7 vs ARCHER 1050: efficacy & dosing
Presented by: Sanjay Popat @drsanjaypopat
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)
Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV
Q3W for 4 cycles (n = 95)
Until disease progression or
unacceptable toxicity
Nivolumab 3mg/kg IV Q2W until disease
progression or unacceptable toxicity
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
Nivolumab 3 mg/kg IV Q2W
(n = 98)a
Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV
Q3W for 4 cycles (n = 61)b
Nivolumab 3 mg/kg IV Q2W
(n = 147)
Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV
Q3W for 4 cycles (n = 95)
Until disease progression or
unacceptable toxicity
Nivolumab 3mg/kg IV Q2W until disease
progression or unacceptable toxicity
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 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
Non-randomized cohort
98 61 n
Randomized cohort
147 95
Non-randomized cohort
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!!!