Plotting the course: optimizing treatment strategies in patients with advanced adenocarcinoma

Pieter E. Postmus University of Liverpool Liverpool, UK Plotting the course: optimizing treatment strategies in patients with advanced adenocarcinoma

Disclosures Advisor Bristol-Myers Squibb AstraZeneca Boehringer Ingelheim Celgene Roche MerckSerono Janssen Clovis Astellas MSD AbbVie G1 Therapeutics Speakers fee Boehringer Ingelheim Pfizer AstraZeneca Eli Lilly MSD Travel support Pfizer Boehringer Ingelheim MSD Celgene

Learning objective After this presentation, participants will be able to describe current and emerging treatment modalities, such as immunotherapy and anti-angiogenic agents, for patients with advanced adenocarcinoma summarize the efficacy and safety of these treatment modalities in recent clinical trials

Question 1 Should every patient be treated with an immunotherapy agent as second-line treatment with adenocarcinoma? 1. Yes, regardless of PD-L1 status 2. No, only in patients who present with PD-L1 positive tumours 3. No, only in patients with PD-L1 positive tumours, EGFR wt, and ALK wt ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; PD-L1, programmed death-ligand 1; wt, wild type.

The view on lung cancer is changing 1990 Lung cancer 2000 Non-small-cell lung cancer Small-cell lung cancer Adenocarcinoma 2008 Adenocarcinoma Large-cell carcinoma Squamous-cell carcinoma Adenocarcinoma and treatable oncogenic alterations with approved drugs (EGFR mutation and ALK translocation) Large-cell carcinoma Small-cell lung cancer Today (2013) Targets today EGFR ALK ROS1 Targets in the future KRAS and others BRAF HER2 RET DDR2 MET and others FGR1 P13K Squamous-cell carcinoma without oncogenic alteration Squamous cell carcinoma with oncogenic alteration Based on Reck M, et al. Lancet. 2013;382:709-19.

Even guidelines have difficulty in keeping up to date

Case discussion: WS, born 1945 Healthy smoker with pain on right side of chest 40 pack-years CT/PET: Mass RUL SUV 20 SUV 16 in left adrenal gland CT-guided biopsy RUL; adenocarcinoma Molecular testing: EGFR negative ALK negative PD-L1 65% CT-guided biopsy adrenal gland; NSCLC (not otherwise specified) CT, computerized tomography; NOS, not otherwise specified; PET, positive-emission tomography; RUL, right upper lobe of lung; SUV, standardized uptake value. Courtesy of P. Postmus.

Case: WS, born 1945 (continued) Courtesy of P. Postmus.

Question 2 What treatment would you recommend? 1. Carboplatin-based doublet 2. Cisplatin + pemetrexed 3. Carboplatin + (nab-)paclitaxel + bevacizumab 4. PD-1/PD-L1 checkpoint inhibitors 5. PD-1/PD-L1 checkpoint inhibitors + chemotherapy

ESMO Guidelines: stage IV non-squamous cell carcinoma Stage IV NSCC ALK translocation Molecular tests EGFR mutation Crizotinib [I, A] No EGFR/ALK mutation Gefitinib [I, A] Erlotinib [I, A] ± bevacizumab [I, A; MCBS 2] Afatinib [I, A] PS 0 1 < 70 years PS 2 < 70 years or PS 0 2 > 70 years PS 3 4 NSCC, non-squamous-cell carcinoma; MCBS, Magnitude of Clinical Benefit Scale, PS, performance status. Based on Novello S, et al. Ann Oncol. 2016;27 Suppl 5:v1-v27.

ESMO Guidelines: stage IV non-squamous cell carcinoma Stage IV NSCC ALK translocation Molecular tests EGFR mutation Crizotinib [I, A] No EGFR/ALK mutation Gefitinib [I, A] Erlotinib [I, A] ± bevacizumab [I, A; MCBS 2] Afatinib [I, A] PS 0 1 < 70 years PS 2 < 70 years or PS 0 2 > 70 years PS 3 4 Based on Novello S, et al. Ann Oncol. 2016;27 Suppl 5:v1-v27.

ESMO Guidelines: stage IV non-squamous cell carcinoma Stage IV NSCC ALK translocation Molecular tests EGFR mutation Crizotinib [I, A] No testing for PD-L1 Gefitinib [I, A] No EGFR/ALK mutation Erlotinib [I, A] ± bevacizumab [I, A; MCBS 2] Afatinib [I, A] PS 0 1 < 70 years PS 2 < 70 years or PS 0 2 > 70 years PS 3 4 Based on Novello S, et al. Ann Oncol. 2016;27 Suppl 5:v1-v27.

ESMO Guidelines: stage IV non-squamous cell carcinoma (no driver mutations) PS 0 1 < 70 years PS 2 < 70 years or PS 0 2 > 70 years 4 6 cycles Cisplatin + pemetrexed [II, A] Cisplatin + gemcitabine [I, B] Cisplatin + docetaxel [I, B] Carboplatin + paclitaxel [I, B] Carboplatin + nab-paclitaxel [I, B] ± bevacizumab 4 6 cycles Carboplatin-based doublets [II, B] Single-agent chemotherapy (gemcitabine, vinorelbine or docetaxel) [I, A] PS 0 1 Partial response or stable disease Maintenance treatment Pemetrexed (switch) [I, B] Pemetrexed (continuation) [I, A] Erlotinib (EGFR-activating mutation) [I, B] ± bevacizumab (if given before) Based on Novello S, et al. Ann Oncol. 2016;27 Suppl 5:v1-v27.

The reality > 80% of patients have no treatable oncogenic alterations 1 Most patients are still in need of systemic treatment 2 Boundary of efficacy reached for chemotherapy 2 Impressive activity of immunotherapy in pretreated patients 2 1. Santabarbara G, et al. Ann Transl Med. 2016;4:215. 2. Personal communication P. Postmus.

PD-L1 expression associated with a favourable outcome with pembrolizumab [Images not shown] PD-L1 expression was assessed using 22C3 pharmdx, which is approved in the in the USA as a companion diagnostic for pembrolizumab 1 For biomarker cutoff selection, PD-L1 expression was reported as the percentage of neoplastic cells indicating staining of PD-L1 in tumor samples from patients with NSCLC 2 TPS > 50% cutoff point was based on KEYNOTE-001 strict determination using independent training and validation sets 2 IHC, immunohistochemistry; PD-1, programmed cell death protein 1; TPS, tumour proportion score. 1. Roach C, et al. Appl Immunohistochem Mol Morphol. 2016;24:392-7. 2. Garon EB, et al. N Engl J Med. 2015;372:2018-28.

RANDOMIZED KEYNOTE-024: study design Patients Untreated stage IV NSCLC Measurable disease ECOG PS 0 1 PD-L1 TPS > 50% No sensitizing EGFR mutations or ALK translocations No treated brain metastases 1:1 N = 305 Pembrolizumab 200 mg every 3 weeks Up to 2 years Platinum doublet every 3 weeks, 4 6 cycles Paclitaxel + carboplatin Pemetrexed + carboplatin Pemetrexed + cisplatin Gemcitabine + carboplatin Gemcitabine + cisplatin (non-squamous histology + pemetrexed maintenance) Primary endpoint: PFS (RECIST v1.1 per blinded, independent central review) Secondary endpoints: OS, ORR, safety Exploratory: Duration of response Progressive disease Crossover a Progressive disease Off study a To be eligible for cross-over, progressive disease had to be confirmed by blinded, independent central radiology review and all safety criteria had to be met. ECOG: Eastern Cooperative Oncology Group; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TPS: tumour proportion score (% of patients with membranous PD-L1 staining on tumour cells). Reck M, et al. N Eng J Med. 2016;375:1823-33.

KEYNOTE-024: PD-L1 screening 1,934 patients entered screening 1,729 submitted samples for PD-L1 assessment 1,653 samples evaluable for PD-L1 500 TPS 50% (30%) 1,153 TPS < 50% Reck M, et al. N Eng J Med. 2016;375:1823-33.

PFS (%) OS (%) KEYNOTE-024: PFS and OS (ITT population) 100 Number at risk Pembrolizumab Chemotherapy 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 154 151 Median PFS (95% CI), months HR (95% CI) p value Pembrolizumab 10.3 (6.7 NR) 0.50 (0.37 0.68) < 0.001 Chemotherapy 6.0 (4.2 6.2) Pembrolizumab Chemotherapy 104 99 Time (months) 89 70 44 18 22 9 3 1 1 0 100 90 80 70 60 50 40 30 20 10 0 Pembrolizumab Chemotherapy 0 3 6 9 12 15 18 21 154 151 136 123 Median OS (95% CI), months HR (95% CI) p value Pembrolizumab NR 0.60 (0.41 0.89) 0.005 Chemotherapy NR 121 106 Time (months) 82 64 39 34 11 7 2 1 Following the recommendation of the external DMC, this trial was terminated early, allowing patients who were previously being treated with chemotherapy to receive pembrolizumab 0 0 Analysis cut-off date: 9 May 2016. CI, confidence interval; DMC, data and safety monitoring committee; HR, hazard ratio; NR, not reached. Reproduced from Reck M, et al. N Eng J Med. 2016;375:1823-33 2016, Massachusetts Medical Society.

ORR (%) (95% CI) KEYNOTE-024: response (ITT population) 1,2 60 50 40 30 20 10 0 CR PR 45% Pembrolizumab Δ 17% p = 0.0011 n = 6 n = 63 28% Chemotherapy n = 1 n = 41 In patients who had an OR: a The median time to response was 2.2 months in both pembrolizumab and chemotherapy groups The median duration of response was not reached in the pembrolizumab group and was 6.3 months in the chemotherapy group, with response ongoing at cut-off Analysis cut-off date: 9 May 2016. a OR was a confirmed CR or PR; assessment was made in accordance with RECIST, version 1.1 by means of blinded, independent, central radiological review. CR, complete response; OR, objective response; PR, partial response. 1. Reck M, et al. N Eng J Med. 2016;375:1823-33. 2. Reck M, et al. Ann Oncol. 2016;27 Suppl 6:abstract LBA8_PR.

KEYNOTE-024: PFS in key subgroups (ITT population) Subgroup Events, n/patients, n HR for disease progression or death (95% CI) Overall 189/305 0.50 (0.37 0.68) Age < 65 years 91/141 0.61 (0.40 0.92) > 65 years 98/164 0.45 (0.29 0.70) Sex Male 116/187 0.39 (0.26 0.58) Female 73/118 0.75 (0.46 1.21) Region of enrolment East Asia 21/40 0.35 (0.14 0.91) Non-East Asia 168/265 0.52 (0.38 0.72) ECOG PS 0 59/107 0.45 (0.26 0.77) 1 129/197 0.51 (0.35 0.73) Histological type Squamous 37/56 0.35 (0.17 0.71) Non-squamous 152/249 0.55 (0.39 0.76) Smoking status Current 44/65 0.68 (0.36 1.31) Former 133/216 0.47 (0.33 0.67) Never 12/24 0.90 (0.11 7.59) Brain metastases at baseline Yes 17/28 0.55 (0.20 1.56) No 172/277 0.50 (0.36 0.68) Platinum-based chemotherapy regimen Included pemetrexed 120/199 0.63 (0.44 0.91) Did not include pemetrexed 69/106 0.29 (0.17 0.50) 0.1 1.0 10 Analysis cut-off date: 9 May 2016. Pembrolizumab better Chemotherapy better Reproduced from Reck M, et al. N Eng J Med. 2016;375:1823-33 2016, Massachusetts Medical Society.

KEYNOTE-024: exposure and AE summary (as-treated population) a Pembrolizumab (n = 154) Chemotherapy (n = 150) Median duration of treatment (range) 7.0 months (1 day 18.7 months) 3.5 months (1 day 16.8 months) Treatment-related AEs, % Any grade Grade 3 5 Any grade Grade 3 5 Any 73 27 90 53 Serious 21 19 21 19 Leading to discontinuation 7 5 11 6 Leading to death 1 1 2 2 Analysis cut-off date: 9 May 2016. a Included all patients who received at least one dose of a trial treatment; for patients in the chemotherapy group who crossed over to the pembrolizumab group after disease progression, only events that occurred during treatment with the assigned chemotherapy regimen are included. AE, adverse event. Reck M, et al. N Eng J Med. 2016;375:1823-33.

OS (%) KEYNOTE-024: updated OS analysis in patients with advanced NSCLC 100 90 80 70 60 50 40 30 20 10 Number at risk Pembrolizumab Chemotherapy 0 0 3 6 9 12 15 18 21 24 Time (months) 154 136 121 112 106 88 57 20 4 151 123 107 88 89 64 35 15 4 a Nominal p value. Data cut-off: 5 January 2017. NE, not estimable. Events, n Pembrolizumab 63 Chemotherapy 84 HR (95% CI) 0.63 (0.46 0.88) p = 0.003 a 70.3% 54.8% 61.2% 43.0% Median (95% CI) NR (19.4 months NE) 14.5 months (9.8 19.6) Brahmer JR. Presented at ASCO 2017; abstract 9000. Reproduced with permission.

Case: WS, born 1945 (continued) April 2017 June 2017 Courtesy of P. Postmus.

Case: WS, 1945 (continued) No toxicity Still responding after 6 cycles Unclear: if progressing, what is the best therapy?

Question 3 If disease progresses, which treatment would you start? 1. Platinum doublet 2. Docetaxel 3. Nintedanib + docetaxel 4. Pemetrexed

Case discussion: BU, born 1955 Adenocarcinoma with pleural effusion Cytology positive Molecular testing: ALK negative EGFR negative PD-L1 0% Response to cisplatin + pemetrexed Maintenance: pemetrexed 8 cycles Mass now growing in LLL LLL, left lower lobe of lung. Courtesy of P. Postmus.

Question 4 What would you do next? Perform another biopsy to re-evaluate for? 1. T790M 2. BRAF 3. ROS1 4. RET 5. PD-L1 6. None of the above

ESMO Guidelines: stage IV non-squamous cell carcinoma Maintenance treatment Pemetrexed (switch) [I, B] Pemetrexed (continuation) [I, A] Erlotinib (EGFR-activating mutation) [I, B] ± bevacizumab (if given before) Disease progression PS 0 2 PS 3 4 BSC Pemetrexed [I, B] Docetaxel [I, B] Nivolumab [I, B; MCBS 5] Pembrolizumab if PD-L1 > 1% [I, A; MCBS 3 if PD-L1 > 1%; MCBS 5 if PD-L1 > 50%] Ramucirumab + docetaxel [I, B; MCBS 1] Nintedanib + docetaxel [II, B] Erlotinib [II, C] Based on Novello S, et al. Ann Oncol. 2016;27 Suppl 5:v1-v27.

Issues around second-line treatment No targetable mutation found? Access to immunotherapy? If yes, is marker analysis needed? Consider need for second biopsy if: not tested initially negative According to ESMO Guidelines, an anti-angiogenic agent, either ramucirumab or nintedanib, in combination with docetaxel is one of the second-line treatment options in patients with advanced adenocarcinoma more likely to be active in early progressors after first-line chemotherapy Novello S, et al. Ann Oncol. 2016;27 Suppl 5:v1-v27.

PFS (%) OS (%) Anti-angiogenic agents as second-line therapy in advanced adenocarcinoma: nintedanib LUME Lung 1: PFS 1 LUME Lung 1: OS 2 100 80 Nintedanib + docetaxel Placebo + docetaxel 100 80 Nintedanib + docetaxel Placebo + docetaxel 60 40 HR (95% CI) = 0.77 (0.62 0.96) p = 0.0193 60 40 20 0 2 4 6 8 10 12 Time (months) 20 HR (95% CI) = 0.83 (0.70 0.99) p = 0.0359 0 0 4 8 12 16 20 24 28 32 36 Time (months) 1. Reck M, et al. Lancet Oncol. 2014;15:143-55. 2. Reproduced from Reck M, et al. Lancet Oncol. 2014;15:143-55 2014, Elsevier Ltd. All rights reserved.

PFS (%) OS (%) Anti-angiogenic agents as second-line therapy in advanced NSCLC: ramucirumab REVEL: PFS 1 REVEL: OS 2 100 80 Ramucirumab + docetaxel Placebo + docetaxel 100 80 Ramucirumab + docetaxel Placebo + docetaxel 60 40 Stratified HR (95% CI) = 0.76 (0.68 0.86) Stratified log-rank p < 0.0001 60 40 20 0 3 6 9 12 15 18 21 Time (months) 20 0 Stratified HR (95% CI) = 0.86 (0.75 0.98) Stratified log-rank p = 0.023 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 1. Garon EB, et al. Lancet. 2014;384:665-73. 2. Reproduced from Garon EB, et al. Lancet 2014;384:665-73 2014, Elsevier Ltd. All rights reserved.

Summary Targeted therapy is an option for approximately 10 15% of patients; new developments are on the way Immunotherapy is first choice for second-line therapy, depending on PD-L1 expression levels for pembrolizumab or nivolumab Pembrolizumab is first choice in previously untreated patients with > 50% PD-L1 positive tumours For PD-L1 0%, standard chemotherapy is still first choice nintedanib + docetaxel for advanced non-squamous NSCLC

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