Incorporating Immunotherapy into the treatment of NSCLC Suresh S. Ramalingam, MD Roberto C. Goizueta Chair for Cancer Research Assistant Dean for Cancer Research Deputy Director, Winship Cancer Institute 1
Outline First-line immunotherapy Salvage therapy Combination approaches Early stage NSCLC Biomarkers 2
Approved Checkpoint Inhibitors for NSCLC Nivolumab Second line therapy for Sq & Non-Sq Pembrolizumab 1 st line therapy for PD-L1 > 50% 1 st line therapy in combination with carboplatin and pemetrexed for non-sq 2 nd line therapy for PD-L1 > 1% Atezolizumab 2 nd line therapy for Sq & Non-Sq 3
Timeline March 2015 Oct' 2015 Oct 2016 May 2017 Nivo 2 nd line Sq Nivo 2 nd line Non-Sq Pembro 2 nd line Pembro 1 st line Atezo 2 nd line Pembro 1 st line (with chemo) 4
Pembrolizumab- 1 st line Stage IV NSCLC PD-L1 > 50% Pembro Chemotx Pembro Chemo RR 45% 28% mpfs 10.3 m 6.0 m OS NR 14.5 m Key aspects: Patient selection Control arm Cross over Reck M, et al, N Engl J Med. 2016;375(19):1823-1833. 5
Pembro Plus Chemotherapy Carboplatin Pemetrexed Stage IV NSCLC Non-Sq Histology Salient points: Sample size Cross over Control arm Outcome by PD-L1 exp Langer CJ, et al. Lancet Oncol. 2016;17(11):1497-1508. Carboplatin Pemetrexed Pembrolizumab Pembro + Chemo Chemo RR 55% 29% mpfs 13 m 8.9 m mos NR NR AE Chemo + Pembro Serious Trtrelated AE (Gr 3-5) Fatigue (any grade) 24% 8% Chemo 64% 40% Rash 27% 15% 6
First-line Immunotherapy Pembrolizumab is approved for patients with PD-L1 expression >50% as monotherapy Pembrolizumab plus chemo is approved for 1 st line treatment of nonsquamous NSCLC Patient selection methods for using combination versus monotherapy are needed Confirmatory studies of chemo plus PD-1/PD-L1 inhibition are awaited 7
Treatment Algorithm for Advanced NSCLC Stage IV NSCLC Molecular testing for EGFR, ALK, ROS1 IHC for PD-L1 Expression EGFR, ALK or ROS1 PD-L1 > 50% No targetable mutation PD-L1 < 50% No Targetable mutation Targeted therapy 1. Pembrolizumab 2. Pembro Plus Chemo (Non-sq) * Bevacizumab/necitumumab added when appropriate 1. Platinum-based chemotherapy* 2. Chemo plus Pembro (Non-sq) 8
Salvage Therapy
Nivolumab Design Response Rate Median PFS Median Survival Nivolumab Vs. Docetaxel (Sq Histology) Nivolumab Vs. Docetaxel (Non-Squamous histology) 20% 9% 19% 12% 3.5 m 2.8 m (HR 0.62, P < 0.001) 2.3 m 4.2 m (HR 0.92, P =0.39) 9.2 m 6.0 m (HR 0.59, P < 0.001) 12. 2 m 9.4 m (HR 0.73, P=0.002) Nivolum ab Brahmer J, et al. N Engl J Med. 2015;373(2):123-135. Borghaei H, et al. N Engl J Med. 2915;373(17):1627-1639. 10
Pembrolizumab Pembrolizumab (2 mg/kg) Vs. Docetaxel 18% 18% 3.9 m 4.0 m (HR 0.88, P = 0.07) 12.7 m 10.4 m (HR 0.71, P=0.0008) Herbst RS, et al. Lancet. 2016;387(10027):1540-1550. 11
Atezolizumab Atezolizumab Vs. Docetaxel 14% 13% 2.8 m 4.0 m (HR 0.95, P=0.49) 13.8 m 9.6 m (HR 0.73, P=0.0003) Rittmeyer A, et al. Lancet. 2017;389(10066):255-265. 12
Combination Approaches
CheckMate 012 Design Rizvi N, et al. Presented at: 17 th World Conference on Lung Cancer. December 6-9, 2015. Denver, Colorado, United States. Abstract ORAL02.05 14
Efficacy by PDL-1 Expression Rizvi N, et al. Presented at: 17 th World Conference on Lung Cancer. December 6-9, 2015. Denver, Colorado, United States. Abstract ORAL02.05 15
Upcoming Advances
PACIFIC Study: Durvalumab in Stage III NSCLC Stage III NSCLC Unresectable Disease Chemotherapy plus RT Durvalumab X 1 Yr Placebo Study met primary endpoint of improved PFS 17
Checkpoint Inhibition in Early Stage NSCLC: ALCHEMIST Scheme Stage IB-IIIA NSCLC Surgery Adj Chemo EGFR Mutation Positive Erlotinib Vs. Obs Molecular Screen EA 4512 ALK Positive Crizotinib Vs Obs Randomize EA5142 EGFR & ALK -ve Nivolumab Vs. Obs 18
Biomarkers
PD-L1 Expression Sica GL, et al. JAMA Oncol. 2017 Mar 9 [Epub ahead of print.] 20
PD-L1 Expression: Assay Performance Sica GL, et al. JAMA Oncol. 2017 Mar 9 [Epub ahead of print.] 21
Mutational Burden as Biomarker Rizvi NA, et al. Science. 2015;348(124-128. 22
Kamphorst AO, et al. Proc Natl Acad Sci U S A. 2017;114(19):4993-4998. 23
Kamphorst AO, et al. Science. 2017;355(6332):1423-1427. 24
Update on Targeted Therapy for NSCLC
ALK+ve NSCLC Crizotinib is superior to chemotherapy for ALK +ve disease Brain metastasis is a common clinical problem Acquired resistance develops in approximately 10 months Need for more effective strategies to achieve better outcomes 26
Ceritinib Vs. Chemotherapy: ASCEND 5 Scagliotti G, et al. Ann Oncol. 2016;27(Suppl 6): Abstract LBA42_PR. 27
PFS Scagliotti G, et al. Ann Oncol. 2016;27(Suppl 6): Abstract LBA42_PR. 28
AE Profiles Scagliotti G, et al. Ann Oncol. 2016;27(Suppl 6): Abstract LBA42_PR. 29
Brigatinib: Activity Against Gatekeeper Mutations Camidge DR, et al. Presented at: 17 th World Conference on Lung Cancer. December 4-7, 2016. Vienna, Austria. Abstract P3.02a-013. 30
ALTA Phase 2 Study Camidge DR, et al. Presented at: 17 th World Conference on Lung Cancer. December 4-7, 2016. Vienna, Austria. Abstract P3.02a-013. 31
J-ALEX Phase III Study Design Key Entry Criteria Stage IIIB/IV or recurrent ALKpositive NSCLC ALK centralized testing (IHC and FISH or RT-PCR) ECOG PS 0-2 1 measurable lesion assessed by investigator Treated/asymptomatic brain metastases allowed 1 prior chemotherapy R 1:1 Alectinib 300 mg BID PO, 28- day cycle (N=100) Crizotinib 250 mg BID PO, 28- day cycle (N=100) Endpoints Primary - PFS assessed by IRF* Secondary - OS - ORR - PK - QOL - CNS PFS - Safety *IRF Independent Review Facility Stratification factors: Clinical stage (IIIB/IV vs. Recurrent) Prior chemotherapy (0 vs. 1) ECOG PS (0/1 vs. 2) Nokihara H, et al. J Clin Oncol. 2016;34(suppl): Abstract 9008. 32
Primary Endpoint: PFS by IRF (ITT Population) Progression-free survival rate (%) 100 80 60 40 20 Alectinib (N=103) Crizotinib (N=104) Events, n (%) 25 (24.3%) 58 (55.8%) Median, mo [95% CI] NR [20.3 - NR] 10.2 [8.2-12.0] P-value <0.0001 HR [99.6826% CI] 0.34 [0.17-0.71] NR 0 No. of patients at risk Alectinib Crizotinib 0 1 3 6 9 12 15 18 21 24 27 103 103 104 102 93 86 10.2 months 76 65 49 40 36 21 27 14 9 4 1 Time (months) Nokihara H, et al. J Clin Oncol. 2016;34(suppl): Abstract 9008. 33
ALEX Study Design Shaw AT, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA9008. 34
ALEX: PFS Shaw AT, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA9008. 35
Shaw AT, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA9008. 36
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Prolonged Progression-Free Survival with Crizotinib Median PFS 19.2 months (95% CI, 14.4 to NR) Shaw AT, et al. N Engl J Med. 371(21):1963-1971. 38
Other Treatable Mutations Target Treatment Results Status RET gene rearrangement Carbozantinib Vandetanib RR 15-40% mpfs 3-7 m In development MET exon 14 mutation Crizotinib RR 44% In development BRAF V600E mutation Dabrafenib + Trametinib RR 65% mpfs 9.5 m Breakthrough status from FDA 39
Dabrafenib Plus Trametinib in BRAF V600E mutated NSCLC Response Rate: 63% Median PFS: 9.7 m Median duration of response: 9 m Planchard D, et al. Lancet Oncol. 2016;17(5):642-650. 40