Updates in Lung Cancer

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1 Updates in Lung Cancer J. Tanner Ringley, PharmD, BCOP, CPP Levine Cancer Institute Learning Objectives: Discuss incorporation of liquid biopsies into practice and interpretation of immunotherapy biomarker assays Evaluate selected trials responsible for new indications in immunotherapy based non-small cell lung cancer (NSCLC) treatment Outline new EGFR-mutant NSCLC treatment recommendations Assess changes in ALK(+)-NSCLC treatment selection Traditional Diagnostic Flow Initiated with multidisciplinary evaluation Patient risk assessment Biopsy timing often dictated by several factors: Tumor location Pt comorbidities Procedure risk Process doesn t fit all patients Tan, W. et al. Non Small Cell Lung Cancer Workup. Medscape 1

Diagnostics Reck, Martin et al. N Engl J Med. 2017;377:849-61.

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possible Patient access to surgical/ir services Results often take longer/ greater chance for delay Dependent on adequate amounts of

2 Diagnostics Reck, Martin et al. N Engl J Med. 2017;377: Liquid Biopsy Two types: -Circulating tumor cells -Plasma based nucleic acid fragments (ie cfdna, mirna, ctdna) Liquid Biopsy Tissue biopsies poses issues Obtaining adequate tissue, multiple procedures possible Patient access to surgical/ir services Results often take longer/ greater chance for delay Dependent on adequate amounts of circulating tumor cells or respective nucleic acid substrate Variable sensitivity and specificity Limited current options available Can be cost prohibitive Current place in therapy? Case by case basis for now Re-testing on progression Mack et al. J Thorac Oncl Suppl Arneth. BMC Cancer :527 2

PD-1/PD-L1 treatment: how hard can it be?

Mario et al. Clin Cancer Res. 2013. (19)2: 1021-1034. Image: www.smartpatients.com/targets/pd-1 PD-L1 Assays: Points to Consider Primary vs.

excisional Time between biopsy and treatment: effect of therapies Definition of positive results Type of cells expressing PD-L1 Location of TILs relative to PD-L1 staining Staining

3 PD-1/PD-L1 treatment: how hard can it be? Large inter-/intra- malignancy type variation in tumor microenvironment Intra-malignancy tissue subtypes Impact on response = next phase of research Opportunity for expertise Sznol, Mario et al. Clin Cancer Res (19)2: Image: PD-L1 Assays: Points to Consider Primary vs. Metastatic disease Tumor biopsy heterogeneity: multiple tumors, multiple passes within a tumor Biopsy type: FNA vs. core vs. excisional Time between biopsy and treatment: effect of therapies Definition of positive results Type of cells expressing PD-L1 Location of TILs relative to PD-L1 staining Staining intensity Distribution: Patchy vs. diffuse, tumoral vs peripheral Expression level can affect drug utilization (ie Pembrolizumab) Current state Common assays: 28-8 assay (Nivolumab), 22c3 assay (Pembrolizumab), SP142 assay (Atezolizumab), SP263 (Durvalumab), & E1L3N (Yale lab test) Providers/supporting staff often unaware of assay being utilized and/or the existence of multiple assays ASCO. Immuno-Oncology 2018 Update. Bramer, J.R. 3

90 NSCLC tissue sample examined by 13 pathologists Specifically developed a standard scoring protocol Results: 28-8(Nivo), 22c3(Pembro), and E1L3n showed concordance SP142(Atezo) significantly lower

Rimm, DL. et al. JAMA Oncol. 2017;3(8):1051-1058. Question 1 A patient presents to your clinic with newly diagnosed advanced NSCLC, and is found to not be a chemotherapy candidate.

4 90 NSCLC tissue sample examined by 13 pathologists Specifically developed a standard scoring protocol Results: 28-8(Nivo), 22c3(Pembro), and E1L3n showed concordance SP142(Atezo) significantly lower mean score for PD-L1 exp Implications: Assure practice is utilizing appropriate test 28-8(Nivo) & 22c3(Pembro) most commonly utilized Be cautious when interpreting assay results to direct tx choice Rimm, DL. et al. JAMA Oncol. 2017;3(8): Question 1 A patient presents to your clinic with newly diagnosed advanced NSCLC, and is found to not be a chemotherapy candidate. The MD initially prescribes Pembrolizumab and sends the patients biopsy for PD-L1 testing (using the 22c3 IHC assay). PD-L1 expression = 60%. The patient turns out to be a self-pay patient, and can luckily qualify for free Atezolizumab through their patient assistance program. What is your recommendation to the MD? A) The tissue was only tested for Pembrolizumab, and would need to be re-tested if selecting another drug. B)Atezolizumab is a viable option in this scenario, given the 22c3 assay showed sufficient expression C)Recommend re-testing with the SP142 assay for Atezolizumab D)Recommend comparative testing of all three assays PACIFIC trial:phase III, placebo-cont, (interim analysis) Pts: Stage III, locally advanced, unresectable, NSCLC, s/p chemo+radiation Durvalumab (anti-pd-l1) vs placebo for 12 month consolidation tx, post-chemo Co-primary endpoints: PFS & OS Secondary endpoints: 12 & 18 month PFS rate, ORR, DOR, time to death or distant metastases, and safety Atonia, S.J., et al. NEJM Nov 16;377(20):

PACIFIC study cont. 713 randomized 709 received treatment 2:1 randomization ( 473 durvalumab, 236 placebo) Durvalumab 10mg/kg IV q2wks x 12 months Results: PFS: 16.8 months vs 5.

5 PACIFIC study cont. 713 randomized 709 received treatment 2:1 randomization ( 473 durvalumab, 236 placebo) Durvalumab 10mg/kg IV q2wks x 12 months Results: PFS: 16.8 months vs 5.6 months 12 month PFS rate: 55.9% vs 33.8% 18 month PFS rate: 44.2% vs 27% Atonia, S.J., et al. NEJM Nov 16;377(20): PACIFIC study cont. ORR: 28.4% vs 16% DOR(@18 months): 72.8% vs 46.8% Time to death or distant metastases: 23.2 months vs 14.6 months Safety: Grade 3/4 AE rate: 29.9% vs 26.1% Discontinuation rate: 15.4% vs 9.8% Brain metastases development (5% vs 11%) Pneumonitis: 6.3% vs 4.3% (not sig) Benefit observed regardless of PD-L1 status, stage IIIa or IIIb, and histologic type Practice Implications: New standard of care Will likely shape design of future trials Rizvi, Naiyer. NEJM : Keynote 189: Double blind, placebo-controlled, Phase III study Pts: treatment naive, metastatic, non-squamous, without sensitizing mutations Pembro/Pem/Platinum vs Placebo/Pem/Platinum Q3wks x 4 cycles Followed by Pembro or Placebo q21 days up to 35 cycles Primary Endpoints: OS & PFS Secondary Endpoints: ORR, DOR, & Safety Ghandi, L. et al. NEJM ;378(22):

6 Keynote-189 cont. OS(12 month): 69.2% vs 49.4% (HR = 0.49) 51% reduction in death Last reported OS (Nov 2017): NR (Pembro) vs 11.3 mo (Placebo) Ghandi, L. et al. NEJM ;378(22): Keynote-189 cont. Improved OS seen across all PD-L1% groups OS benefit positive correlation with PD-L1% Ghandi, L. et al. NEJM ;378(22): Keynote-189 cont. Median PFS (12 month): 34.1% vs 17.3% (8.8 mo vs 4.9 mo) Median PFS benefit correlated with PD-L1% TPS>50% = 9.4 mo TPS<1% = 6.1 mo Ghandi, L. et al. NEJM ;378(22):

7 Keynote-189 cont. ORR: 47.6% vs 18.9% ORR correlated with PD-L1% TPS>50% ORR = 61.4% vs TPS<1% ORR = 32.3% Median DOR: 11.2 mo vs 7.8 mo Safety: Grade 3/4 AE rate: 67.2% vs 65.8% Acute kidney injury: 5.2% vs 0.5% Nephritis: 1.7% vs 0% Practice implications: Superior OS, irrespective of PD-L1% Addition of immune-related AEs New standard of care Ghandi, L. et al. NEJM ;378(22): Question 2 63yo male w/ newly diagnosed, unresectable, stage IIIa, NSCLC. Driver mutations tests returned negative, and the patient was not deemed a candidate for radiation therapy. The patient has controlled T2DM with stage II CKD as the only complication. What would be the most appropriate therapy? A) Paclitaxel 200mg/m2 + Carboplatin AUC=6 IV q21days x 4 cycles B) Paclitaxel 50mg/m2 + Carboplatin AUC=2 weekly x 6 cycles, followed by Durvalumab 10mg/kg IV q2wks x 12 months C) Cisplatin 75mg/m2 + Docetaxel 75mg/m2 q21days x 4 cycles D) Cisplatin 75mg/m2 + Pemetrexed 500mg/m2 IV q21 days x 4 cycles Checkmate 227: Open label, multipart, Phase 3 study Pts: Stage IV or recurrent NSCLC not previously treated with chemotherapy, w/ high tumor mutational burden Dual arm study: PD-L1>1% vs PD-L1<1% PD-L1>1% randomized 1:1:1 Nivo+Ipi/Nivo/Chemo PD-L1<1% randomized 1:1:1 Nivo+Ipi/Nivo+chemo/Chemo Stratified: Squamous vs Non-squamous Hellmann, MD. et al. NEJM May 31;378(22):

8 Hellmann, MD. et al. NEJM May 31;378(22): Tumor Mutational Burden Somatic mutation prevalence in tumor cell DNA Associated with accumulation of neo-antigens Increased immune system recognition of tumor cells Attracts tumor-infiltrating lymphocytes (TILs) Checkmate-026: Nivo failed to improve OS over chemo, 1 st line Subgroup analysis: Improved PFS in high TMB tumors Alexandrov, Ludmil et al. Nature August 22; 500(7463): Checkmate 227 cont. Co-primary endpoints: Ipi/Nivo vs chemo PFS (blinded-independent review) in population selected for TMB OS in population selected for PD-L1 expression status Secondary endpoints: PFS in Ipi/nivo vs. chemo in pts with high TMB & PD-L1>1% Exploratory endpoints: ORR, DOR, and safety Chemo selection: histological based platinum doublet Stable non-squamous: allowed to continue pemetrexed or pemetrexed/nivolumab maintenance No Crossover permitted Hellmann, MD. et al. NEJM May 31;378(22): Checkmate 227 cont. N=1739 pts, 1004 pts assessed for TMB, 444 pts high TMB No correlation seen between TMB level and PD-L1 status PFS in pts w/ low TMB: (not-sig. HR=1.07) Ipi/Nivo = 3.2 months Chemo = 5.5 months PFS in pts w/ high TMB: (sig. difference) Ipi/nivo = 7.2 months Chemo = 5.5 months 8

Checkmate 227 Final Thoughts Benefit not seen in low-tmb patients PFS was significantly better in the high-tmb subgroup Regardless of PD-L1 status and histological type Establishes TMB as possible

9 Checkmate 227 Final Thoughts Benefit not seen in low-tmb patients PFS was significantly better in the high-tmb subgroup Regardless of PD-L1 status and histological type Establishes TMB as possible response & outcome biomarker NNT ~ 4 to 5 patients in high TMB group Safety was not significantly different across groups Greater immune related AEs w/ Ipi/nivo Greater grade 3/4 events w/ chemo Are we ready for full immuno? diagnostics lacking Missed opportunity? - sequential chemo/immuno Hellmann, MD. et al. NEJM May 31;378(22): EGFR-TKI Landscape 1 st /2 nd gen EGFR-TKIs have been 1 st line standard T790M mutation detected in >50% EGFR(+)-NSCLC progression cases Osimertinib approved in 2015 for T790M(+) NSCLC Osimertinib up to 200x greater affinity for exon-19 del & T790M mutations 3 rd gen - decreased affinity for wild type EGFR Dong, Lijun, et al. Oncotarget (8) p FLAURA trial: Double blind, phase 3 study, interim analysis Pts: Untreated, EGFR-mutant (+), advanced, NSCLC Dual arm study: 1:1 randomization Osimertinib 80mg qd Standard EGFR-TKI (Erlotinib 150mg/Gefitinib 250mg) Primary endpoint: Investigator-assessed PFS Secondary endpoints: OS, ORR, DOR, disease control rate, depth of response, and safety Soria, JC, et al. NEJM Jan 11;378(2):

10 Soria, JC, et al. NEJM Jan 11;378(2): FLAURA trial cont. PFS and OS was significantly better with Osimertinib in all subgroups AEs grade 3 or higher: 34%(Osi) vs 45% (standard TKI) Standard EGFR-TKI adverse events occurred less w/ Osimertinib (ie rash, diarrhea, dry skin, stomatitis) No significant difference in rate of discontinuation, dose interruption, and/or dose reduction FLAURA trial cont. Duration of response: 17.2(Osi) vs 8.5 months Also showed slightly better initial tumor size reduction PFS in pts w/ CNS mets: 15.2(Osi) vs 9.6 months Osimertinib previously outperformed chemo in CNS metastatic NSCLC Greater BBB penetrance vs 1 st /2 nd gen EGFR-TKIs Clinical consensus: Osimertinib first line for all? No T790M, exhaust 1 st /2 nd gen choices first Tx after progression on Osimertinib? Osimertinib 1 st line, clonal selection for other mutations? Patient by patient basis: CNS mets vs early stage dx Soria, JC, et al. NEJM Jan 11;378(2): Question 3 72yo patient with Stage IV, metastatic NSCLC. Recent cranial imaging confirmed multiple brain metastases, and biomarker testing reveals an EGFR exon19 deletion (+), T790M mutation (-). The patient is otherwise healthy with no significant comorbidities. What is the most appropriate therapy choice? A) Start with erlotinib first line until disease progression and/or acquired resistance. B) Start with afatinib first line until disease progression and/or acquired resistance. C) Start with gefitinib first line until disease progression and/or acquired resistance. D) Start with osimertinib first line until disease progression and/or acquired resistance. 10

ALEX trial: randomized, open label, phase 3 study Pts: untreated, ALK-positive, advanced, NSCLC Dual arm study: randomized 1:1 Alectinib 600mg bid Crizotinib 250mg bid Primary endpoint:

11 ALEX trial: randomized, open label, phase 3 study Pts: untreated, ALK-positive, advanced, NSCLC Dual arm study: randomized 1:1 Alectinib 600mg bid Crizotinib 250mg bid Primary endpoint: Investigator-assessed PFS Secondary endpoints: independent-review PFS, time to CNS progression, ORR, and OS Peters, S, et al. NEJM Aug 31;377(9): ALEX trial cont. Primary: PFS significantly improved median = 17.7 mo vs 11.1 mo OS trended in favor of alectinib HR 0.76, p=0.24 Benefit was consistent across all subgroups No significant difference in dose intensity Grade 3 or higher adverse events: 41%(Alect) vs 50%(Crizot) No significant difference in overall and serious adverse event rates across both groups Alectinib: Anemia, myalgia, elev t-bili, photosensitivity Crizotinib: Nausea, diarrhea, vomiting Peters, S, et al. NEJM Aug 31;377(9): ALEX trial cont. Time to CNS progression longer w. Alectinib (HR=0.16) CNS progression events: 18 pts(alect) vs 68 pts(crizot) ALK(+)-NSCLC increased rate of CNS mets at diagnosis and/or lifetime risk of CNS disease Alectinib high CNS penetrance not PGP substrate Implications: Alectinib 1 st line Improved outcomes regardless of CNS involvement Crizotinib still niche in ROS-1 ALK(+) niche very dynamic Peters, S, et al. NEJM Aug 31;377(9):

12 Question 4 Which of the following is true based on the results of the ALEX trial (alectinib vs crizotinib) in ALK(+) NSCLC? A)The CNS progression was significantly lower in the alectinib trial arm B) The primary endpoint investigated was overall survival C) Crizotinib showed a lower adverse event rate D) Progression free survival was not significantly different between the two treatment arms Pilot study Neoadjuvant Nivolumab in untreated, early stage(i, II, or IIIa), resectable NSCLC Primary endpoint: Safety and Feasibility Secondary endpoint: Pathological response, PD-L1% 21 pts rec d two treatments of Nivolumab 3mg/kg IV, 4 wks prior to surgery Low & acceptable side effect profile, no surgery delays Major pathological response in 9 pts (45%) and complete response in 3 pts Correlation between pre-treatment tumor mutational burden and pathological response Forde, P.M., et al. NEJM May 24;378(21): Forde, P.M., et al. NEJM May 24;378(21):

13 Forde, P.M., et al. NEJM May 24;378(21): ASCO Update: Keynote-042 Pembrolizumab vs platinum-based chemotherapy as first line treatment for advanced/metastatic NSCLC with PD- L1 TPS ( 1%) Primary endpoint: OS 1274 pts (637 per arm), PD-L1% groups of >50%, >20%, and > 1% Demonstrated superiority to chemo in OS improvement Lopes, G, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA4). ASCO Update: Keynote-407 Pembrolizumab combined w/ Carboplatin + Paclitaxel/nab-Paclitaxel as first-line treatment for squamous NSCLC Primary Endpoint: OS Significantly improved OS vs chemo alone Risk of death decreased by 36% (HR = 0.64, p=0.0008) Benefit consistent across subgroups, regardless of PD-L1 expression Showed ORR improvement over chemo alone 58.4% vs 35% 5 th study showing improved survival benefit with Pembrolizumab in advanced NSCLC Paz-Ares, LG, et al. J Clin Oncol 36, 2018 (suppl; abstr 105). 13

14 Small Cell Lung Cancer: ROVA-T Rovalpituzumab tesirine DLL3 targeted antibody-drug conjugate DLL3 = biomarker found on approx. 80% of tumor initiating cells in small cell lung cancer Initial phase 1 study showed promising results Phase 2 (TRINITY) results released March, 2018 Investigate efficacy as 3 rd line option Failed to meet proposed ORR cutoff Abbvie not seeking accelerated approval Small cell lung cancer still lacking in research advancement Rudin, CM, et al. Lancet Oncol Jan;18(1):42-51 Tropomysin receptor kinase (TRK) fusion proteins found in many cancer types Primary endpoint: ORR Secondary endpoint: DOR, PFS, and safety 55 pts (ages 4 months to 74 yo) 17 unique TRK-fusion (+) tumor types (4 NSCLC) ORR = 75%, DOR = 71% at 1 year, 55% PFS at 1 year NSCLC pts showed large tumor reductions Median DOR and PFS not yet reached Most AEs grade 1, grade ¾ <5% Drilon, A, et al. NEJM Feb 22;378(8): Refrences Reck, Martin et al. Precision Diagnosis and Treatment of Non-Small Cell Lung Cancer.N Engl J Med 2017;377: Arneth, Borros. Update on the types and usage of liquid biopsies in the clinical setting: a systematic review. BMC Cancer :527. Mack, P et al. Clinical Utility of Circulating Tumor DNA (ctdna) Analysis by Digital next Generation Sequencing of over 5,000 Advanced NSCLC Patients. J Thorac Oncl Suppl : s Rizvi, Naiyer. Immunotherapy for Unresectable Stage III Non Small-Cell Lung Cancer. NEJM : Sznol, M. et al. Antagonist Antibodies to PD-1 and B7-H1 (PD-L1) in the Treatment of Advanced Human Cancer. Clin Cancer Res Mar 1; 19(5): ASCO. Immuno-Oncology 2018 Update. Bramer, J.R. Available at: Rimm, DL. et al. A Prospective, Multi-institutional, Pathologist-Based Assessment of 4 Immunohistochemistry Assays for PD-L1 Expression in Non Small Cell Lung Cancer. JAMA Oncol. 2017;3(8): Atonia, S.J., et al. Durvalumab after Chemoradiotherapy in Stage III Non Small-Cell Lung Cancer. NEJM Nov 16;377(20): Rizvi, Naiyer. Immunotherapy for Unresectable Stage III Non Small-Cell Lung Cancer. NEJM : Ghandi, L. et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. NEJM ;378(22):

15 References Hellmann, MD. et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. NEJM May 31;378(22): Alexandrov, Ludmil et al. Signatures of mutational processes in human cancer. Nature August 22; 500(7463): Dong, Lijun, et al. Clinical strategies for acquired epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small-cell lung cancer patients. Oncotarget (8) p Soria, JC, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non Small-Cell Lung Cancer. NEJM Jan 11;378(2): Peters, S, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non Small-Cell Lung Cancer NEJM Aug 31;377(9): Forde, P.M., et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. NEJM May 24;378(21): Lopes, G, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) 1%: Open-label, phase 3 KEYNOTE-042 study. Clin Oncol 36, 2018 (suppl; abstr LBA4). Paz-Ares, LG, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol 36, 2018 (suppl; abstr 105). Rudin, CM, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol Jan;18(1):42-51 Drilon, A, et al. Efficacy of Larotrectinib in TRK Fusion- Positive Cancers in Adults and Children. NEJM Feb 22;378(8):

Updates in Lung Cancer. J. Tanner Ringley, PharmD, BCOP, CPP Levine Cancer Institute

Updates in Lung Cancer. J. Tanner Ringley, PharmD, BCOP, CPP Levine Cancer Institute Updates in Lung Cancer J. Tanner Ringley, PharmD, BCOP, CPP Levine Cancer Institute Learning Objectives: Discuss incorporation of liquid biopsies into practice and interpretation of immunotherapy biomarker