in metastatic nsclc optimal sequence of …carbone dp, et al. n engl j med. 2017 jun...

OPTIMAL SEQUENCE OF IMMUNOTHERAPY IN METASTATIC NSCLC

PIYADA SITTHIDEATPHAIBOON, M.D.Division of Medical Oncology. Department of Medicine.

The King Chulalongkorn Memorial Hospital.

Does immunotherapy work differently in the first-line and subsequent settings?

Benefit for EGFR TKI in subsequent lines of therapy in EGFR-Mutated Patients

Rosell, et al. N Engl J Med 2009;361(3): 958-67.

Chemotherapy EGFR TKI

EGFR TKI Chemotherapy

What are the implications of giving a first-line EGFR TKI in EGFR Mutated disease?

Death

Death

Patients who receive only one line of

therapy

First-line EGFR TKI

Rapid worsening

First-line chemotherapy

Theoretical survival

PD

PD

Rapid worsening

EGFR Mut+ NSCLC

Advantage from using first-line EGFR TKI

After first-line platinum doublet chemotherapy, only 50–60% of patients receive second-line therapy1

Delaying EGFR TKI therapy therefore risks the possibility that patients die sooner, and never benefit from the most effective treatment2

1. Stinchcombe, et al. JTO 2009; 2. Gridelli, et al. Clin Lung Cancer 2011

Optimal sequence of immunotherapy in metastatic NSCLC

Chemotherapy ImmunotherapyR

Immunotherapy Chemotherapy

Pembrolizumab in Adv NSCLC (KEYNOTE-001): Survival Outcomes for First Line vs Later Lines

PFS

Garon EB, et al. N Engl J Med. 2015;372:2018-2028.

Populations ORR% Median DoR, mos Median PFS, mos Median OS, mos

All patients 19.4% 12.5 3.7 12

Previously-treated 18% 10.4 3 9.3

Previously untreated 24.8% 23.3 6 16.2

OS

Nivolumab

Docetaxel

Squamous IIIB/IV

(N = 272)

Immune Checkpoint Inhibitors in Pretreated Adv NSCLC: Randomized Trials

CheckMate 017 CheckMate 057 KEYNOTE 010

OAK

Nonsquamous IIIB/IV

(N = 582)

Nivolumab

Docetaxel

Adv NSCLC with≥ 1% PD-L1+ TPS

(N = 1034)

Pembrolizumab(2 mg/kg)

Docetaxel

Pembrolizumab(10 mg/kg)

Adv NSCLC (2L/3L)

(N = 1225)

Atezolizumab

Docetaxel

Brahmer J, et al. N Engl J Med. 2015 Jul 9;373(2):123-35. Borghaei H, et al. N Engl J Med. 2015 Oct 22;373(17):1627-39.Herbst RS, et al. Lancet. 2016 Apr 9;387(10027):1540-50. Rittmeyer A, et al. Lancet. 2017 Jan 21;389(10066):255-265.

Barlesi F, et al. Lancet Oncol. 2018 Nov;19(11):1468-1479. D.M. Kowalski, et al. ESMO 2018.

JAVELIN Lung 200

Adv NSCLCIIIB/IV

(N = 792)

Avelumab

Docetaxel

ARCTIC

Adv NSCLC (≥3L)

Durvalumab

SOC

≥25% PD-L1 TC(N = 126)

<25% PD-L1 TC(N = 469)

Durvalumab

SOC

Tremelimumab

Durva + Trem

Immune Checkpoint Inhibitors in Pretreated Adv NSCLC: OS


CheckMate 017 CheckMate 057

KEYNOTE 010 OAK

No “Cross-Over” Effect

JAVELIN Lung 200

Barlesi F, et al. Lancet Oncol. 2018 Nov;19(11):1468-1479.

≥1% PD-L1+

Immune Checkpoint Inhibitors in Pretreated Adv NSCLC: Subsequent treatment

Study Treatment Arm Systemic therapy, % Chemotherapy, % Immunotherapy, %

CheckMate 017 Nivolumab 36% 36% 1%

Docetaxel 30% 24% 2%

CheckMate 057 Nivolumab 42% 61% <1%


KEYNOTE 010 Pembro 2 mg/kg 40% 35% 1%


OAK Atezolizumab 48.5% 41% 4.5%


JAVELIN Lung 200 Avelumab 40% NA 6%

Docetaxel 48% NA 26%


Barlesi F, et al. Lancet Oncol. 2018 Nov;19(11):1468-1479.

OS by PD-L1 expression


CheckMate 017 CheckMate 057

KEYNOTE 010 OAK

KEYNOTE 010: PD-L1 ≥50%

Herbst RS, et al. Lancet. 2015;387:1540-1550.

Treatment Arm Median PFS (95% CI), mo

HR (95% CI) P

Pembro 2 mg/kg 5.0 (4.0-6.5) 0.59 (0.44-0.78) 0.0001

Pembro 10 mg/kg 5.2 (4.1-8.1) 0.59 (0.45-0.78) <0.0001

Docetaxel 4.1 (3.6-4.3) - -

Pembrolizumab

Platinum-doublet


(N = 305)

Immune Checkpoint Inhibitors in Un-treated Adv NSCLC: Randomized Trials

KEYNOTE 024 KEYNOTE 042 CheckMate 026

MYSTIC

Reck M, et al. N Engl J Med. 2016;375:1823-1833. Lopes G, et al. ASCO 2018. Abstract LBA4. Carbone DP, et al. N Engl J Med. 2017 Jun 22;376(25):2415-2426. N A Rizvi, et al. ESMO 2018. Abstract LBA6.


(N = 541)

Nivolumab

Platinum-doublet

Pembrolizumab

Platinum-doublet


(N = 1274)

Adv NSCLC withAll comers(N = 1118)

Durvalumab

Platinum-doublet

Durvalumab + Tremelilumab

IMpower 110

Non-Squamous IIIB/IV with ≥1%

PD-L1+(N = 400)

Atezolizumab

Platinum-doublet

IMpower 111

Squamous IIIB/IV with ≥1% PD-L1+

(N = 400)

Atezolizumab

Platinum-doublet

Await for results

KEYNOTE 024: Pembrolizumab vs CT as First-line Therapy for Advanced NSCLC in PD-L1 ≥50%

PFS


HR (95% CI) P Median OS (95% CI), mo

HR (95% CI) P

Pembrolizumab 10.3 (6.7–NR) 0.50 (0.37–0.68)

<0.001 Not reached 0.60 (0.41–0.89)

0.005

Chemotherapy 6.0 (4.2–6.2) Not reached

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

OS

44% cross-over to Pembrolizumab

KEYNOTE 042: Pembrolizumab vs CT as First-line Therapy for Advanced NSCLC in PD-L1 ≥50%

Lopes G, et al. ASCO 2018. Abstract LBA4.



HR (95% CI) P

Pembrolizumab 7.1 (5.9-9.0) 0.81 (0.67-0.99

0.0170* 20.0 (15.4-24.9) 0.69 (0.56-0.85

0.0003

Chemotherapy 6.4 (6.1-6.9) 12.2 (10.4-14.2)

*Not positive; did not cross multiplicity-adjusted threshold for significance: P ≤ .01455. †Formal comparison not performed per hierarchical testing strategy which required PD-L1 TPS ≥ 50% to be positive.

PFS OS

KEYNOTE-042: OS in PD-L1 TPS ≥ 1% Population (Primary Endpoint)


KEYNOTE-042: OS in PD-L1 TPS 1-49% Populations (Exploratory Analysis)


PD-L1 ≥50% subgroup (≈50%) is the main driver of OS benefit.Pembrolizumab is NOT established standard in PD-L1 1-49%.

CheckMate-026: Nivolumab vs CT as First-line Therapy for Advanced NSCLC in PD-L1 ≥5% (Primary Endpoint)

PFS

• No PFS/OS benefit even in pts with ≥ 50% PD-L1

OS

Carbone DP, et al. N Engl J Med. 2017 Jun 22;376(25):2415-2426.

CheckMate-026: PFS by TMB subgroups (Exploratory Analysis)

• OS was similar between groups regardless of TMB (68% cross-over to nivolumab)

Carbone DP, et al. N Engl J Med. 2017 Jun 22;376(25):2415-2426.

High TMB Low/Medium TMB

MYSTIC: Durvalumab ± tremelimumab vs CT as First-line Therapy for Advanced NSCLC in PD-L1 ≥25%

N A Rizvi, et al. ESMO 2018. Abstract LBA6.

Durvalumab vs CT Durva + tremelimumab vs CT

Potential for synergy with combination therapy

Boosting the Potential for Immune Response With Combination Therapies

ControlTargeted therapies

Immune checkpoint blockadeCombinations/sequencing

Surv

ival

TimeSu

rviv

alTime

?

Where We Are Now Where We Want to Be

Ribas A, et al. Clin Cancer Res. 2012;18:336-341.

Pembrolizumab + Platinum-Pemetrexed

Platinum-Pemetrexed

Non-SQ stage IV

All comers(N = 616)

Immune Checkpoint Inhibitors Combination in Un-treated Adv NSCLC: Randomized Trials

KEYNOTE 189 IMpower 130 IMpower 132

KEYNOTE 407

Gandhi L, et al. N Engl J Med. 2018 May 31;378(22):2078-2092. Cappuzzo F, et al. ESMO 2018 Abstract LBA53. Papadimitrakopoulou VA, et al. WCLC 2018. Abstract OA05.07. Paz-Ares L, et al. N Engl J Med. 2018 Nov

22;379(21):2040-2051. Robert M, et al. ASCO 2018 Abstract LBA 9000.

Non-SQ stage IV

All comers (N = 578)

Atezolizumab + Platinum-Pemetrexed

Platinum-Pemetrexed

Atezolizumab + Platinum-nabPaclitaxel

Platinum-nabPaclitaxel

Non-SQ stage IV

All comers (N = 723)

IMpower 131

Pembrolizumab + Platinum-(nab)Paclitaxel

Platinum-(nab)Paclitaxel

Squamous IVAll comers (N = 559)

Squamous IVAll comers (N = 1021)

Atezolizumab + Platinum-Paclitaxel

Platinum-nabPaclitaxel

Atezolizumab + Platinum-nabPaclitaxel

KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum as First-line Therapy for Advanced non-squamous NSCLC

PFS



HR (95% CI) P

Pembro-chemo 8.8 (7.6–9.2) 0.52(0.43-0.64)

<0.001 Not reached 0.49 (0.38–0.64)

<0.001

Chemotherapy 4.9 (4.7–5.5) 11.3 (8.7-15.1)

Gandhi L, et al. N Engl J Med. 2018 May 31;378(22):2078-2092.

OS

41.3% cross-over to Pembrolizumab or IO

KEYNOTE-189: OS by PD-L1

Gandhi L, et al. N Engl J Med. 2018 May 31;378(22):2078-2092.

KEYNOTE-407: Carboplatin-(Nab)Paclitaxel With or Without Pembrolizumab in First-Line Metastatic Squamous NSCLC

PFS



HR (95% CI) P

Pembro-chemo 6.4 (6.2–8.3) 0.56(0.45-0.70)

<0.001 15.9 (13.2-NR) 0.64 (0.49–0.85)

<0.001

Chemotherapy 4.8 (4.3–5.7) 11.3 (9.5-14.8)

Paz-Ares L, et al. N Engl J Med. 2018 Nov 22;379(21):2040-2051.

OS

32% cross-over to Pembrolizumab or IO

KEYNOTE-407: OS by PD-L1

Paz-Ares L, et al. N Engl J Med. 2018 Nov 22;379(21):2040-2051.

Simultaneously inhibiting the CTLA-4 and PD-L1 pathways has potential for synergistic immune effects

Melero I, et al. Nat Rev Cancer. 2015;15:457-472. Drake CG. Ann Oncol. 2012;23:viii41-viii46.

CheckMate 227: Nivolumab + Ipilimumab vs Platinum-Doublet Chemotherapy as First-line Treatment for Advanced NSCLC

Hellmann MD, et al. N Engl J Med. 2018 May 31;378(22):2093-2104.

CheckMate 227: Nivolumab + Ipilimumab vs Platinum-Doublet Chemotherapy as First-line Treatment for Advanced NSCLC

Hellmann MD, et al. N Engl J Med. 2018 May 31;378(22):2093-2104.

High TMB (≥10 mut/Mb) Low TMB (<10 mut/mb)

MYSTIC: Durvalumab ± tremelimumab vs CT as First-line Therapy for Advanced NSCLC in PD-L1 ≥25%

N A Rizvi, et al. ESMO 2018. Abstract LBA6.

Rationale for Combining anti-PDL1 + Bevacizumab + Chemotherapy

• In addition to its known anti-angiogenic effects1, bevacizumab’s inhibition of VEGF has immune modulatory effects2

1. Ferrara N, et al. Nat Rev Drug Discov, 2004. 2. Hegde PS, et al. Semin Cancer Biol. 2017. 3. Gabrilovich DI, et al. Nat Med, 1996. 4. Oyama T, et al. J Immunol, 1998. 5. Goel S, et al. Physiol Rev, 2011. 6. Motz GT, et al. Nat Med, 2014.

7. Hodi FS, et al. Cancer Immunol Res, 2014. 8. Wallin JJ, et al. Nat Commun, 2016. 9. Zitvogel L, et al. Immunity, 2013. 10. Gabrilovich DI, Nagaraj S. Nat Rev Immunol, 2009. 11. Roland CL, et al. PLoS One, 2009. 12. Facciabene A, et al. Nature, 2011.

13. Voron T, et al. J Exp Med, 2015. Figure adapted from Chen DS, Mellman I. Immunity, 2013.

IMpower150: Efficacy of Atezolizumab Plus Bevacizumab and Chemotherapy in 1L Metastatic Nonsquamous NSCLC

Socinski MA, et al. N Engl J Med. 2018 Jun 14;378(24):2288-2301.

IMpower150: PFS Benefit in Arm B vs C in the ITT-WT (Primary Endpoint)

Socinski MA, et al. N Engl J Med. 2018 Jun 14;378(24):2288-2301.

in metastatic nsclc optimal sequence of …carbone dp, et al. n engl j med. 2017 jun...

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