rethinking second line therapy in the io era · ram+doc pl+doc number at risk 0 3 6 9 12 15 18 21...

Rethinking Second Line Therapy in the IO Era

Edward B Garon, MD, MSAssociate Clinical Professor

Director of Thoracic Oncology ProgramDavid Geffen School of Medicine at UCLA

Director of Signal Transduction and TherapeuticsJonsson Comprehensive Cancer Center at UCLA

November 23, 2019

DisclosuresFunding to my institution from the following companies for clinical trials: AstraZenca, Bristol Myers Squibb, Dynavax, Eli Lilly, EMD Serono, Genentech, Iovance, Mirati, Merck, Neon, NovartisPaid advisory board/steering committee positions: Dracen, EMD Serono, Novartis

Options in patients prior to availability frontline PD-(L)1 inhibitor chemo combinations

Docetaxel in Previously Treated NSCLC

• Median OS– Docetaxel 7.0 mo– BSC 4.6 mo– Log-rank P = 0.047

• Median TTP– Docetaxel 10.6 wk– BSC 6.7 wk– P < 0.001

• Docetaxel ORR 7.1%Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2193.

TAX 317 Trial

Docetaxel 75 mg/m2 (n = 55)BSC (n = 49)

Cum

ulat

ive

Prob

abilit

y of

Sur

viva

l

Months

Pemetrexed vs Docetaxel in Previously Treated Patients – OS

Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.

Phase III REVEL: Study Design

Abbreviations: Bev=bevacizumab; ECOG PS=Eastern Cooperative Oncology Group performance status; ORR=objective response rate; PFS=progression-free survival; ROW=rest of the world; q3wks=every 3 weeks.

- Stage IV NSCLC after one platinum-

based chemo +/-maintenance

- Prior Bev allowed- All histologies

- PS 0 or 1- Treated brain mets

allowed

Treatment until disease progression

or unacceptable toxicity

Ramucirumab 10 mg/kg +

Docetaxel 75 mg/m2 q3wksN=628

Placebo +

Docetaxel 75 mg/m2 q3wksN=625

RANDOMIZE

1:1

Stratification factors:• ECOG PS 0 vs 1

• Gender • Prior maintenance• East-Asia vs. ROW

Primary endpoint: Overall Survival

Secondary endpoints:PFS, ORR, safety, patient-reported outcomes

Garon E et al. The Lancet. 384 (9944): 665–673, 23 August 2014

Progression-Free SurvivalITT Population, Investigator Assessment

Median (95% CI) Censoring Rate

RAM+DOC vs PL+DOC

4.5 (4.2-5.4) 11.1%3.0 (2.8-3.9) 6.7%

Stratified HR (95% CI) = 0.762 (0.677-0.859)Stratified log-rank P < .0001

RAM+DOCPL+DOC

Prog

ress

ion-

Free

Su

rviv

al (%

)

RAM+DOCPL+DOC

Number at risk

RAM+DOCPL+DOCCensored

0 3 6 9 12 15 18 21 24 27 30 33

383301

204172

12095

5937

3817

119

74

33

32

00

00

36Survival Time (months)

628625

00

0

20

40

60

80

100


Overall SurvivalITT Population Median (95% CI) Censoring Rate

RAM+DOC

RAM+DOC vs PL+DOC

10.5 (9.5-11.2) 31.8%PL+DOC 9.1 (8.4-10.0) 27.0%

Stratified HR (95% CI) = 0.857 (0.751-0.979)Stratified log-rank P = .0235

0

20

40

60

80

100

Ove

rall

Surv

ival

(%)

RAM+DOCPL+DOC

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33

527501

415386

329306

231197

156129

10386

7056

4536

2323

119

20

36Survival Time (months)

628625

00

RAM+DOCPL+DOCCensored


REVEL: Conclusions • OS and PFS improvement were consistent in most major subgroups,

including squamous and nonsquamous histology

• Safety profile was as expected for an anti-VEGFR agent in combination with DOC

• Ramcirumab with docetaxel was FDA approved for platinum-refractory NSCLC in December 2014

Garon et al. The Lancet. 384 (9944): 665–673, 23 August 2014

LUME-Lung 1 Study DesignNintedanib 200mg BID p.o., D2–21,

+ Docetaxel 75mg/m2 IV, D1,21-day cycles (n=655)

Placebo BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,

21-day cycles (n=659)N=1314

RANDOMIZE

Stratification: ECOG PS (0 vs 1)Prior bevacizumab (yes vs no)

Histology (squamous vs non-squamous)Brain metastases (yes vs no)

Stage IIIB/IVor recurrent

NSCLC patients after 1st line

chemotherapy(all histologies)

1:1

PD

PD

Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy

Regions: Europe / Asia / South AfricaAccrual: Dec 23, 2008 to Feb 9, 2011

Reck M. Lancet Oncol. 2014 Feb;15(2):143-55.

LUME Primary Endpoint: PFS Independent Central Review in All Patients

100

80

60

40

20

0

Prob

abili

ty o

f pro

gres

sion

free

su

rviv

al (%

)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18Time (months)

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 3.4 2.7HR (95% CI) 0.79 (0.68 to 0.92)p-value 0.0019

No. at riskNintedanib 565 470 295194 155 9 57 19 4 4 3 1 0

Placebo 569 478 250144 11670 43 21 2 1 1 0 0


LUME Secondary Analysis- OS

A- Adeno 9 mosB- AdenoC- All


Non-docetaxel based options that emerged after immunotherapy

• Immunotherapy– For all good PS patients without contraindications– KN-010, CM 017 & 057, OAK

• Platinum doublet– For patients who received single agent ICI

• Pemetrexed– For patients who received ABCP first line

MA11.03: Pembrolizumab Plus Docetaxel Increases Progression-Free Survival Compared with Docetaxel Alone in Previously Treated Advanced Non-Small Cell Lung Cancer Patients – Arrieta OG,

et al• Study objective

– To investigate the efficacy and safety of pembrolizumab + docetaxel compared with docetaxel alone in patients with advanced NSCLC

Arrieta OG, et al. J Thorac Oncol 2019;14(suppl):Abstr MA11.03

PD/toxicity

Key patient inclusion criteria• Advanced NSCLC

• Progressed after platinum-based chemotherapy

• Regardless of mutation or PD-L1 status

• ECOG PS 0–1 (n=78)

Docetaxel 75 mg/m2 D1 q3w (up to 6 cycles)

(n=38)

Pembrolizumab 200 mg D8 + docetaxel 75 mg/m2 D1

q3w (up to 6 cycles)(n=40)

Primary endpoint• ORR

Secondary endpoints• PFS, OS, safety

R1:1

Pembrolizumab maintenance

PD/toxicity

MA11.03: Pembrolizumab Plus Docetaxel Increases Progression-Free Survival Compared with Docetaxel Alone in Previously Treated Advanced Non-Small Cell Lung Cancer

Patients

• Key results– ORR was 42.5% in the pembrolizumab + docetaxel arm vs. 15.8% in the docetaxel alone arm

(OR 3.9, 95%CI 1.34, 11.15; p=0.01)– ORR in pretreated patients with EGFR mutations was 58.3% in the pembrolizumab + docetaxel

arm vs. 23.1% in the docetaxel alone arm


PFS in all patients PFS in patients with EGFR mutationsTreatment No. (events) Median, mo (95%CI)

P + D 40 (20) 9.5 (4.2, NR)

D 38 (10) 3.9 (3.2, 5.7)

EGFR(+) No. (events) Median, mo (95%CI)

P + D 12 (4) 6.8 (6.2, NR)

D 13 (8) 3.5 (2.3, 6.2)

PFS,

%

Time, months

1.0

0.80.6

0.4

0.2

0

0

4038

3

3225

6

215

9

141

12

100

15

80

18

60

21

50

30

00

No. at riskP + D

D

24

30

27

10

PFS,

%

Time, months

1.0

0.80.6

0.4

0.2

0

0

1213

3

85

6

62

9

30

12

10

15

10

18

10

21

10

30

00

No. at riskP + D

D

24

10

27

00

HR 0.26 (95%CI 0.07, 92.6); p=0.037HR 0.24 (95%CI 0.13, 0.46); p<0.001

MA11.03: Pembrolizumab Plus Docetaxel Increases Progression-Free Survival Compared with Docetaxel Alone in Previously Treated

Advanced Non-Small Cell Lung Cancer Patients – Arrieta OG, et al

• Conclusion– In patients with advanced NSCLC, pembrolizumab

combined with docetaxel appears to be effective with improved ORR and PFS compared docetaxel alone, although it is associated with higher rates of pneumonitis and hypothyroidism


AEs, n (%)Pembrolizumab + docetaxel

(n=40)Docetaxel

(n=38) p-value

Most commonFatigueAnaemiaNausea

26 (65.0)26 (65.0)21 (52.5)

24 (63.2)19 (50.0)18 (47.4)

Non-immune-relatedHypomagnesemiaLymphopenia

0 (0)8 (20.0)

7 (18.4)0 (0)

0.004<0.004

Immune-relatedPneumonitisHypothyroidism

9 (22.5)11 (27.5)

2 (5.3)1 (2.6)

0.0290.002

…but the world has changed

Lisberg A and Garon EB. J Clin Oncol 2019;37(7):529-536

Options in patients in the current treatment paradigm

Oligo-progression after response to front-line ICI

• 26 patients progressing after immunotherapy at a median of 313 days– Only 9 1st line– 2 y OS from acquired resistance – 70%

• Oligo-metastatic progression limited to 1 or 2 sites in ~88% of cases • 54% continued ICI beyond PD• 77% with nodal PD including > half of those with nodal only PD • Radiation to progressive disease in 58%, most while continuing ICI

– 2-year survival 92%.

Gettinger et al J Thorac Oncol 2018 13: 831

Small observational studies of RAM/DOC after ICI

Second and third line combinations after ICI

• Nintedanib + docetaxel – 390 pts on nintedanib named use program

• 11 had prior platinum doublet then ICI followed by 3rd line nintedanib/doce

• PR in 4 patients, DCR 82%, PFS 3.2 mo• Ramucirumab + docetaxel

– ORR with RAM/doce after IO compared to before IO– 66.7% vs 39.5% (P = .03)

• Combination chemotherapy– 73 pts underwent chemotherapy after ICI– ORR 53.4% compared to 34.9% to chemo before ICI– Platinum doublet 66.7% vs 39.5%– Single agents 46.9% vs 25%

Corral J et al Clin Transl Oncol 2019:21:1270Shiono A et al Thorac Cancer 2019:10;775

Park S et al, J Thorac Oncol. 2018;13:106-11

ORR 60%DCR 90%PFS 169

daysOS

343 days

Efficacy of ramucirumab and docetaxel given either before or after immune checkpoint inhibitors in patients with lung cancers

Offin M et al ABS 9078 ASCO 2019

• Paraphrased Abstract: RamDoce is approved for NSCLC after platinum-based therapy. Past data suggest a possible differential response to chemotherapy based on ICI exposure.

• Methods: Pts with stage IV NSCLC who received RamDoce at MSK from 1/2015 - 6/2018 (n = 194) before (78) or after (116) ICI

• Median line of therapy for RamDoce in both cohorts was 3.

• Conclusions: There was no difference in TTD or OS for RamDoce when given before or after ICI. There was a trend toward prolonged benefit from RamDoce in EGFR/KRAS-mutant lung cancers. Data on the efficacy of RamDoce in oncogene-driven groups can help guide care and serve as a benchmark for new drug evaluations.

DOI: 10.1200/JCO.2019.37.15_suppl.9078 Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019) 9078-9078.

Before ICI After ICI PFemale 45 53 0.56Ever smoker 50 96 0.004Median age 59 64 0.003Adenocarcinoma 73 103 0.30TTD/OS 1.5m/1.6y 3m/2y 0.39/0.49

IASLC WCLC 2018

Retrospective analysis

135 pts in 11 Japanese centers

Docetaxel/RAM second line and

beyond

July 2016-Nov 2018

MA07.06: Immunotherapy Re-Challenge After Nivolumab Treatment in Advanced Non-Small Cell Lung Cancer

in French Real-World Setting• Study objective

– To investigate the efficacy and safety of rechallenge with nivolumab in patients with advanced NSCLC

• Methods– Data were collected from the National hospitals database (PMSI) for patients with advanced

NSCLC (n=10,452) who began treatment with nivolumab between 2015 and 2016 and were followed until December 2017

– Treatment discontinuation was defined as having missed ≥3 infusions– Patients who were rechallenged were stratified according to the duration from their first

nivolumab treatment: <3, 3–6 and ≥6 months– Immunotherapy (IO) retreatment was defined as ‘IO resumption’ or ‘IO rechallenge’

depending on the use or not, respectively, of chemotherapy prior to the second immunotherapy cycle

– Time-to-treatment discontinuation (TTD) and OS were assessedLevra MG, et al. J Thorac Oncol 2019;14(suppl):Abstr MA07.06

MA07.06: Immunotherapy Re-Challenge After Nivolumab Treatment in Advanced Non-Small Cell Lung Cancer in French Real-World Setting

• Key results– Of the 5118 patients receiving a second cycle of therapy, 1517 received IO– 45.8% had a median duration of first IO treatment <3.5 months

Levra MG, et al. J Thorac Oncol 2019;14(suppl):Abstr MA07.06

IO rechallengeIO resumption Months Median OS, months (95%CI)<3 11.8 (10.2, 13.9)3–6 15.6 (12.7, 20.0)≥6 NR (16.2, NA)

No. at risk

<3 mo3–6 mo≥6 mo

Time since resumption of IO, months

Ove

rall

surv

ival

, %

100

80

60

40

20

00

485296346

6

294202161

12

1549352

18

50278

24

144–

30

100

Time since start of IO rechallenge, months

Ove

rall

surv

ival

, % 80

60

40

20

00

2109486

6

1295838

12

70272

18

3814–

24

8––

30

Months Median OS, months (95%CI)<3 13.1 (11.2, 18.4)3–6 NR (19.9, NA)≥6 NR (NA, NA)

p<0.001(Log-rank test)

p<0.005(Log-rank test)

MA07.06: Immunotherapy Re-Challenge After Nivolumab Treatment in Advanced Non-Small Cell Lung Cancer in French Real-World Setting

• Conclusions– In patients with advanced NSCLC, around

30% of those patients who had discontinued the first immunotherapy either had nivolumab resumption or rechallenge

– Survival outcomes were promising during a second cycle of immunotherapy, particularly in those who received prior treatment for 3 months or more

Levra MG, et al. J Thorac Oncol 2019;14(suppl):Abstr MA07.06

Dual Checkpoint InhibitionPF

S R

ate

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20

PD-L1 ≥25%

PD-L1 <25%PD-L1

unknown

No. of patients at risk Time (months)26 9 7 5 3

34 10 6 6 5 4 2 2 1 1

18 11 6 3 2 2 2 1 1

PD-L1 <25%34 (30)

1.7(1.6–1.8)

PD-L1 ≥25%26 (22)

1.7(1.6–4.0)

Unknown18 (14)

3.1(1.7–5.4)

Number of patients (n events)Median PFS (months)

(95% CI)

Progression-free Survival

0 0 0 0 0 0

0

0 0

Garon et al. ASCO 2018

ConclusionsIn a post-immunotherapy setting, there is a resurgence of interest in second line chemoLocal therapies are an optionWhether immunotherapy “primes” subsequent therapies is debatedThere are limited benefits to immunotherapy rechallenge or combinations to date

rethinking second line therapy in the io era · ram+doc pl+doc number at risk 0 3 6 9 12 15 18 21...

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