Immunotherapy for the Treatment of Lung Cancer Corey J

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Immunotherapy for the Treatment of Lung Cancer Corey J. Langer, MD, FACP University of Pennsylvania, Philadelphia, PA 19104 Disclosures

• Abbott, Amgen Inc., ARIAD Pharmaceuticals, Inc., AstraZeneca Pharmaceuticals LP, Bayer AG, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corporation, CarisDx, Clariant, Clovis Oncology, Eli Lilly and Company, Genentech, Inc., Incyte Corporation, Madrigal Pharmaceuticals, Inc., Novartis AG, Peregrine Pharmaceuticals Inc., Pfizer, SWOG, Vertex Pharmaceuticals Incorporated, Consulting Fees • ARIAD Pharmaceuticals, Inc., Celgene Corporation, Clovis Oncology, GlaxoSmithKline, Merck & Co., Inc., Contracted Research • Amgen, Synta, Peregrine, SWOG, Incyte, Lilly, DSMC Members • I will not be discussing non-FDA approved indications during my presentation. Immune checkpoint inhibitors in NSCLC

Nivolumab PD-1

Pembrolizumab 2017 (April) 2016 (Fall) PD-1 Pembrolizumab + 2015 (Fall) Pembrolizumab pemetrexed and FDA approved carboplatin Atezolizumab Nivolumumab 1st line NSCLC 2015 (March) Approved in Fall FDA approved for 2nd line Non- (PD-L1 > 50%) Nivolumab FDA st sq NSCLC 1 line NSCLC PD-L1 2012 approved in 2nd Pembrolizumab FDA approved Checkmate line Sq NSCLC Pembrolizumab in 2nd line 017 and 057 FDA approved 2008 nd NSCLC (PDL1 > initiated in 2 line Nivolumab NSCLC 1%) Pembrolizum FIH trial (PD-L1 > 50%) Atezolizumab ab FIH trial initiated FDA approved initiated 2nd line NSCLC CA209-003 5-Year Update: Phase 1 Nivolumab in Advanced NSCLC

100 Median OS (95% CI), mo 80 Overall (N = 129) 9.9 (7.8, 12.4) 60 1 y OS, 42% OS (%) OS 40 2 y OS, 24% 3 y OS, 18% 5 y OS, 16% 20

0 0 1 2 3 4 5 6 7 8

No. at Risk Years 129 49 27 20 17 16 3 1 0

Brahmer et al, AACR 2017 PD1/PD-L1 Inhibitors increase Overall Survival in 2L Advanced NSCLC

CHECKMATE 017 CHECKMATE 057

KEYNOTE 010 (TPS ≥ 1%) OAK

Brahmer NEJM 2015 Borghaei, NEJM 2015 Herbst Lancet 2016. Rittmeyer Lancet 2017 KEYNOTE 010: Pembrolizumab approval > 2nd line (PD-L1 > 1%)

PD-L1 tumor proportion score 50% 204/442 0.53 (0.40-0.70) 1%–49% 317/591 0.76 (0.60-0.96) Tumor sample Archival 266/455 0.70 (0.54-0.89) New 255/578 0.64 (0.50-0.83) Histology Squamous 128/222 0.74 (0.50-1.09) Adenocarcinoma 333/708 0.63 (0.50-0.79) EGFR status Mutant 46/86 0.88 (0.45-1.70) Wild type 447/875 0.66 (0.55-0.80) 0.1 1 10 Favors Pembrolizumab Favors Docetaxel

Herbst et al, Lancet 2015 EGFRm PD-(L)-1 meta-analysis

CK Lee et al., JTO 2016 Toxicities in 2/3L Randomized trials

Atezolizumab Nivolumab Nivolumab Keynote 010 OAK SQ: CM 017 NSQ:CM 057 (updated OS; 2L) (updated OS; 2/3L)

Related Grade 15% 8% 11% 13-16% 3-5 AEs Discontinuation due to related 5% 6% 6% 4-5% AEs Pneumonitis 1% 5% 3% 4-5% AEs Rittmeyer, et al., Lancet 2017 Brahmer, et al., NEJM 2015 Borghaei, et al., NEJM 2015 Herbst, et al., Lancet 2015 PD-L1 selection to bridge the gap? KEYNOTE-024 Study Design (NCT02142738)

Key Eligibility Criteria Pembrolizumab • Untreated stage IV NSCLC 200 mg IV Q3W • PD-L1 TPS ≥50% (2 years) • ECOG PS 0-1 R (1:1) • No activating EGFR mutation or N = ALK translocation 305 • No untreated brain metastases Platinum-Doublet PDa Pembrolizumab • No active autoimmune disease Chemotherapy 200 mg Q3W requiring systemic therapy (4-6 cycles) for 2 years

Key End Points Primary: PFS (RECIST v1.1 per blinded, independent central review) Secondary: OS, ORR, safety Exploratory: DOR Reck M et al, ESMO 2016, NEJM 10/16 Efficacy data: Keynote 24

48%

15%

imaging every 9 weeks  Clear and strong signal of activity  ORR is improved, with a control arm that performs as expected (based on other phase III trials)  45% ORR is the one of best RRs ever reported in 1st line setting (and with monotherapy!)  Time to Response is identical between Pembro and Chemo  PFS is improved by 4.3 months (HR of 0.50)  Improvement of PFS in all subgroups (except female/never smokers => lower mutational load ?)  Strongest signal of PFS benefit observed in SqCC (HR of 0.35)

Reck M et al, ESMO 2016, NEJM 10/16 Keynote 24: Survival data

• Clearcut survival benefit • Estimated rate of OS @ 12 months: 70% (Pembro) vs 54% (CT) • HR for death: 0.60 • Despite cross-over in 50% of patients on the control arm

Reck M et al, ESMO 2016, NEJM 10/16 Mutation Burden Determines Sensitivity to PD-1 Blockade in NSCLC

*partial or stable response lasting > 6 mo

Rizvi N et al, Science 2015:348(6230):124-128 PFS by Tumor Mutation Burden Subgroup CheckMate 026 TMB Analysis Nivolumab in First-line NSCLC High TMB Low/medium TMB Nivolumab Chemotherapy Nivolumab Chemotherapy n = 47 n = 60 n = 111 n = 94 100 100 Median PFS, months 9.7 5.8 Median PFS, months 4.1 6.9 90 (95% CI) (5.1, NR) (4.2, 8.5) 90 (95% CI) (2.8, 5.4) (5.5, 8.6)

80 HR = 0.62 (95% CI: 0.38, 1.00) 80 HR = 1.82 (95% CI: 1.30, 2.55) 70 70

60 60

50 Nivolumab 50 PFS (%) PFS 40 40

30 30 Chemotherapy Chemotherapy 20 20

10 10 Nivolumab

0 0 0 3 6 9 12 15 18 21 0 3 6 9 12 15 18 21 24 Months Months No. at Risk Nivolumab 47 30 26 21 16 12 4 1 111 54 30 15 9 7 2 1 1 Chemotherapy 60 42 22 15 9 7 4 1 94 65 37 23 15 12 5 0 0 Peters, et al., AACR 2017 PACIFIC (NCT02125461/D4191C00001): Study Design

• Phase 3, randomized, double-blind, placebo-controlled, multicenter, global study (26 countries)

Patients with locally advanced Arm 1 (n=468): unresectable NSCLC (Stage III) Durvalumab i.v. 10 mg/kg q2w in a consolidation setting (N=702) for up to 12 months Absence of progression following R 2:1 at least 2 cycles of platinum-based chemotherapy concomitant with radiation Arm 2 (n=234): therapy Placebo i.v. q2w

Primary endpoints • PFS, OS Est. completion: 2017 Secondary endpoints FPD4 Q2 14 • ORR, DoR, DSR LPCD: Q2 16 • Safety/tolerability • PK, immunogenicity, QoL

DoR = duration of response; DSR = deep sustained response; FPD, first patient dosed; i.v. = intravenous; LPCD = last patient commenced dosing; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 15 PK = pharmacokinetics; q2w = every 2 weeks; QoL = quality of life. PACIFIC (NCT02125461/D4191C00001): Study Design

• Phase 3, randomized, double-blind, placebo-controlled, multicenter, global study (26 countries)

Primary endpoints • PFS, OS Est. completion: 2017 Secondary endpoints FPD4 Q2 14 • ORR, DoR, DSR LPCD: Q2 16 • Safety/tolerability • PK, immunogenicity, QoL

DoR = duration of response; DSR = deep sustained response; FPD, first patient dosed; i.v. = intravenous; LPCD = last patient commenced dosing; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 16 PK = pharmacokinetics; q2w = every 2 weeks; QoL = quality of life. EA5142: ANVIL – Adjuvant Nivolumab in Resected NSCLC

Co-primary endpoints: DFS and OS in all patients

17 Combination Immune checkpoint blockade

PD-L1

A, N Engl J Med 2012; 366:2517-2519. Ipilimumab: Nivolumab: CTLA-4 PD-1 Combination I-O (IPI/NIVO) potential in first line ?

CheckMate 012 Goldman, et al, ASCO Annual Meeting, 2017 KEYNOTE-021 Cohort G

Pembrolizumab 200 mg Q3W for 2 years Key Eligibility Criteria + • Untreated stage IIIB or IV Carboplatin AUC 5 mg/mL/min nonsquamous NSCLC + Pemetrexed 500 mg/m2 • No activating EGFR mutation or Q3W for 4 cyclesb ALK translocation R (1:1)a • Provision of a sample for N=12 PD-L1 assessmenta 3 • ECOG PS 0-1 • No untreated brain metastases Carboplatin AUC 5 mg/mL/min PD Pembrolizumab • No ILD or pneumonitis requiring + Pemetrexed 500 mg/m2 200 mg Q3W systemic steroids Q3W for 4 cyclesb for 2 years

End Points Primary: ORR (RECIST v1.1 per blinded, independent central review) Key secondary: PFS Other secondary: OS, safety, relationship between antitumor activity and PD-L1 TPS

Langer, et al Lancet Oncology 2016 Confirmed Objective Response Rate (RECIST v1.1 by Blinded, Independent Central Review)

Δ26% Pembro + Chemo 100 Chemo Alone P = 0.0016 90 Responders Responders 80 n = 33 n = 18 55% 70 TTR, mo 1.5 2.7 60 median 50 (1.2-12.3) (1.1-4.7) 29% (range) 40 DOR, mo 30 NR NR median ORR, % ORR, % (95% CI) 20 (1.4+-13.0+) (1.4+-15.2+) (range) 10 0 Ongoing Pembrolizumab Chemotherapy response, 29 (88) 14 (78) Data cut-off: August 8, 2016. a n (%)

DOR = duration of response; TTR = time to response. aAlive without subsequent disease progression.

Langer, et al Lancet Oncology 2016 PFS and OS Survival data

Clear PFS benefit and no OS advantage • Median PFS improved by 4.1 months • PFS HR is 0.53 • No difference for OS (crossover; immature data……..) • Estimated rate of OS @ 12 months: 75% (Combo) vs 72% (CT) • In CT arm cross-over is 51% to PD-(L)1 therapies (pembro & others) Updated (ASCO ‘17): • RR: 57% vs 30.5% • PFS HR has dropped to 0.5 from 0.53, Median now NR vs 8.9 • OS HR has dropped to 0.69 from 0.9 with dip in p value from 0.37 to 0.13 (1yr OS 76% vs 69%) Langer, et al Lancet Oncology 2016, Papadimitrikopolou, ASCO 2017 Study Design

Patients: R • Metastatic non- A squamous NSCLC Carboplatin/Cisplatin • First line metastatic N Pemetrexed treatment D Pembrolizumab • Measurable disease O 200 mg Q3W • ECOG PS 0-1 Pemetrexed X4 cycles PD Follow • Tissue for biomarker M Pembrolizumab available I • EGFR wild type Z • EML4/ALK fusion A negative Carboplatin/Cisplatin T • No active CNS Pemetrexed Pembrolizumab metastases I +Saline Pemetrexed O X4 cycles +Saline PD Stratify: N • PDL1 prop score: ≥1%, <1% • Smoking status 2:1 Primary Endpoint: PFS – target HR 0.7 • cisplatin vs carboplatin Secondary Endpoints: OS, ORR, AE N=570 Exploratory Endpoints: QoL

24 Study Design

25 Phase 3 first-line combination trials in advanced NSCLC (all PD-L1 unselected) Case Study #1

A 58-year-old female never smoker with bilateral lung mets, biopsy shows adenocarcinoma, EGFR mutation (L858R) and PD-L1 is 90% positive (22C3 assay). What do you recommend?

1. Erlotinib 150 mg po qd 2. Pembrolizumab 3. Pembrolizumab + pemetrexed and carboplatin combination Case Study #2 A 70-year-old female ex-smoker with NSCLC with treatment response to anti-PD-1 antibody presents with increasing cough, SOB and new decline in O2 sat to 82%. What is your management recommendation ? 1. Continue anti-PD-1 antibody Baseline 4 months 2. Continue anti-PD-1 with post dose reduction 3. Hold anti-PD-1 for 2 weeks 4. Discontinue anti-PD-1 and start prednisone 40 mg po qd 5. Discontinue anti-PD-1 and admit for IV steroids Additional Case Studies Clinical Scenario: PDL1 (+) NSCLC > 50%

HPI: 77F former heavy smoker with Hx/ HFrEF (EF 20% w/ ICD), CHF, mature B-cell neoplasm (most likely lymphoplasmacytic lymphoma) causing myelophthisic pancytopenia found to have a LLL mass on follow up PET scan on November 10, 2016. Bronchoscopy of the left lower lobe mass, revealed a poorly differentiated squamous cell carcinoma. • In January 2016 she complained of weakness and was found to have progressive pancytopenia. She declined bone marrow biopsy at that point and was supported with transfusions for a presumed diagnosis of MDS. • She was admitted to HUP in July 2016 with fevers. Bone marrow at that time revealed a mature B-cell neoplasm (CLL/SLL vs lymphoplasmacytic lymphoma). • She was also noted to have a left lung infiltrate at that time, thought to represent a fungal pneumonia. She was treated with antibiotics, voriconazole and rituximab. Testing for aspergillus antigen and beta D glucan was negative; there was no microbiologic diagnosis of fungal infection. She improved clinically. Interval Hx 01/10/17: Seen by Dr. Schuster • She completed a four week course of Rituxumab on August 4, 2016, at which point, she felt much better, no longer requiring weekly transfusions. • Howver, PET/CT on November 10, 2016 showed an enlarging FDG avid mass in the left lower lobe with maximum SUV 8.5. She was completely asymptomatic. No other complaints. 75 yo WF with Hx Cardiomyopathy, low grade NHL and newly diagnosed NSCLC

11/16 Clinical Scenario: PDL1 (+) NSCLC > 50%

Current Hx • She was seen in pulmonary clinic by Dr. Vachani and underwent bronchoscopic biopsy of the left lower lobe lung mass. Pathology showed a poorly differentiated squamous cell carcinoma. • She was determined to have stage IIIA squamous cell lung cancer. She was recommended to undergo concurrent chemoradiation. Clinical Scenario: PDL1 (+) NSCLC > 50%

Current Hx • She was seen in pulmonary clinic by Dr. Vachani and underwent bronchoscopic biopsy of the left lower lobe lung mass. The pathology showed a poorly differentiated squamous cell carcinoma. • She was determined to have stage IIIA squamous cell lung cancer. She was recommended to undergo concurrent chemoradiation. • PDL1 testing returned strongly (+) at 80% Clinical Management: How would you treat this patient, who is “highly chemo-averse?” 1. Local XRT alone 2. Concurrent chemoradiation with weekly Paclitaxel/Carboplatin 3. Induction Tx with Pembrolizumab, followed by XRT +/- Pac/Carbo after “max” response 4. Pembrolizumab alone Clinical Scenario: PDL1 (+) NSCLC > 50%

Interval Hx 01/17/17: No new complaints. Seen by Cardiology, who feels her CHF and low EF are well compensated and believe she can withstand the rigors of combined modality therapy. Interval brain MRI (-) for CNS mets. Seen by Dr. Schuster in interim; he was a bit dubious pt would opt for standard combined modality chemoXRT. Since found to have PDL1 (+) tumor; wonders if PD1 MAb might be an option, either alone or in combination with XRT. Interval Hx 01/26/17: Discussed at Tumor board. Induction therapy with Pembro favored in lieu of either chemo or upfront XRT +/- Chemo. Feels good today, more strength and energy. No new complaints. Interval History 3/16/17: Eileen returns in follow-up for cycle 3 Pembro. She is doing well, has some left eye swelling. Took a dose of lasix but did not help.; No vision changes. No priuritis. She c/o mild nausea for few days but took medication and it helped. Interval Hx 04/06/17: Transient nausea, decreased with ondansetron, ice pops. No diarrhea, DOE. Otherwise tolerating Tx extremely well. Remains very active with no compromise in stamina or function. Eager to keep going with Pembro and Rituxumab Interval Hx 06/22/17: Ffollow-up with a PET scan post six cycles of Pembro, which she is tolerating well x for ~ 5-7 days of nausea and fatigue after therapy. Sense of well being intact. No rash or itch or diarrhea or arthritic Sx or any other complaints. Performance Status, Karnofsky : 100 75 yo WF with Hx Cardiomyopathy, low grade NHL and newly diagnosed NSCLC

11/16 06/17 Synopsis: PDL1 (+), Tx-Naïve NSCLC Initial Hx: 11/23/16 • 75 y.o. male former smoker (1-1.5 ppd x 20 yrs quit 1980) initially presented with right shoulder, back and chest pain. He thought he had pulled a muscle in the back; Sx were accompanied by night sweats. CXR obtained 11/21/16 showed a 4 x 3 cm cm RML/RUL perihilar opacity. • He was seen by thoracic surgeon who recommended completion of staging and tentative RMLobectomy or bilobectomy. • CT scan performed on 11/23/2016 showed a 4.7 cm spiculated mass in the right middle lobe extending across the minor fissure into the right upper lobe. • PET/CT showed FDG-avid RUL/RML pulmonary nodule, with nodular pleural thickening, right hilar LAD, bilateral indeterminate pulmonary nodules, and diffuse osseous metastases including sternum, bilateral ribs, right glenoid, pelvis, and spine. • 11/28/16 Brain MRI revealed isolated left anterosuperior insular/subinsular 5 mm, probable metastasis with mild associated vasogenic edema, but minimal mass effect. No midline shift or herniation. No other evident metastases in the brain. • Pt underwent bronchoscopy for BAL of RML and biopsy of level 11 LN. Tumor proved (+) for adenoca, solid pattern TTF1 (+). • Tissue was sent for molecular testing and PDL1 profiling • He received denosumab and SRS to the brain lesion Initial Questions

1. What’s the patient’s stage? 1. I 2. II 3. III 4. IV 2. What do you do next? a. Do you wait for testing to return? b. Or do you empirically start treatment? 3. If “b”, which regimen? Synopsis: PDL1 (+), Tx-Naïve NSCLC Initial Hx: 11/23/16 • 75 y.o. male former smoker (1-1.5 ppd x 20 yrs quit 1980) initially presented with right shoulder, back and chest pain. He thought he had pulled a muscle in the back; Sx were accompanied by night sweats. CXR obtained 11/21/16 showed a 4 x 3 cm cm RML/RUL perihilar opacity. • He was seen by thoracic surgeon who recommended completion of staging and tentative RMLobectomy or bilobectomy. • CT scan performed on 11/23/2016 showed a 4.7 cm spiculated mass in the right middle lobe extending across the minor fissure into the right upper lobe. • PET/CT showed FDG-avid RUL/RML pulmonary nodule, with nodular pleural thickening, right hilar LAD, bilateral indeterminate pulmonary nodules, and diffuse osseous metastases including sternum, bilateral ribs, right glenoid, pelvis, and spine. • 11/28/16 Brain MRI revealed isolated left anterosuperior insular/subinsular 5 mm, probable metastasis with mild associated vasogenic edema, but minimal mass effect. No midline shift or herniation. No other evident metastases in the brain. • Pt underwent bronchoscopy for BAL of RML and biopsy of level 11 LN. Tumor proved (+) for adenoca, solid pattern TTF1 (+). • Tissue was sent for molecular testing and PDL1 profiling • He received SRS to the brain lesion and denosumab Interval Hx 12/12/16: • Over the preceding 2-3 wks, pain improved, but did not resolve. He noted epistaxis after denosumab, which spontaneously resolved. Appetite remained intact. There were no sequelae post SRS. • PDL1 testing returned (+) at 80%. All molecular markers, including ALK, EGFR, ROS1 etc. were (-) How would you have treated this pt prior to 10/16?

1. Pembrolizumab 2. Nivolumab 3. Carboplatin/Paclitaxel/Bevacizumab 4. Carboplatin/Pemetrexed/Bevacizumab 5. Carboplatin/Pemetrexed/Pembrolizumab 6. Carboplatin/Pemetrexed 7. Carboplatin/Gemcitabine How would you have treated this pt prior to 10/16?

11/23/16 02/14/17