Histology: Its Influence on Therapeutic Decision Making

Histology: Its Influence on Therapeutic Decision Making Mark A. Socinski, MD Professor of Medicine and Thoracic Surgery Director, Lung Cancer Section, Division of Hematology/Oncology Co-Director, UPMC Lung Cancer Center of Excellence and Lung and Thoracic Malignancies Program University of Pittsburgh

Disclosures Advisory Committee Contracted Research Speakers Bureau Bristol-Myers Squibb Company, Daiichi Sankyo Inc, Lilly Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Genentech BioOncology, GlaxoSmithKline, Lilly, Merck, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche Laboratories Inc, Synta Pharmaceuticals Corp Celgene Corporation, Genentech BioOncology

Overview of NSCLC Histologies NSCLC adenocarcinoma Adenocarcinoma is a malignant epithelial tumor with glandular differentiation or mucin production, showing acinar, papillary, bronchoalveolar, or solid with mucin growth patterns or a mixture of these patterns. NSCLC large cell carcinoma Large cell carcinoma is an undifferentiated non-small cell carcinoma that lacks the cytologic and architectural features of small cell carcinoma and glandular or squamous differentiation. NSCLC squamous cell carcinoma Squamous cell carcinoma is a malignant epithelial tumor showing keratinization and/or intercellular bridges that arise from bronchial epithelium. These features vary with degree of differentiation, being prominent in well-differentiated tumors and focal in poorly differentiated tumors. Diagnostic Accuracy influenced by type of biopsy procedure, quantity of tumor in the specimen, degree of tumor differentiation, use of ancillary studies, experience of the pathologist Images copyright 2007 Asterand PLC Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARCPress. 2004:26-30.

EASY CASES- MORPHOLOGY IS SUFFICIENT SCLC ADC SQC NOT SO EASY CASES IHC SHOULD HELP SQC- basaloid ADC-solid pattern LCNEC

IMMUNOHISTOCHEMISTRY AND NSCLC MARKER ADENOCARCINOMA SQUAMOUS CELL CARCINOMA CK 7 ~90 ~20-30 CK5/6 10-20 ~100 P63 10-20 ~100 TTF-1 70-90 Almost never P40 Almost never ~100 Cytokeratin 20, Napsin A, surfactant A, Ber-EP4, B72.3, synaptophysin, chromogranin, CD56, CEA

IMMUNOHISTOCHEMISTRY AND NSCLC- SMALL SPECIMENS IHC 1 SQC/1 ADC and/or mucin ADC IHC + or mucin+ SQC IHC - SQC IHC + ADC IHC + or mucin+ SQC IHC + ADC IHC - or mucin- IHCmucin - NSCLC, favor ADC NSCLC, favor SQC NSCLC,NOS possible adenosquamous NSCLC,NOS

Small Biopsies/Mixed Histology Confidence in the diagnosis aids therapeutic choices.talk to your pathologist Clearly sampling bias is an issue When uncertain, clinical factors must be considered - smoking status, age, co-morbidities, PS, etc Optimize cytotoxic choices based on.. - efficacy (ORR, PFS, OS benefits) - toxicity Second pathologic opinions can be helpful

5 Reasons Why Medical Oncologists Care About Histology Reason #1 Bevacizumab Reason #2 Pemetrexed Reason #3 Molecular testing Reason #4 nab-paclitaxel Reason #5 - Necitumumab

Reason #1: Bevacizumab in NSCLC: Bleeding in Randomized Phase II Trial 6 life-threatening pulmonary hemorrhages; 4 fatal Overall incidence: 9% (6/66) 5 occurred at bevacizumab 7.5 mg/kg Apparent risk factors Baseline hemoptysis Histology Squamous histology: 31% (4/13) Nonsquamous histology: 4% (2/53) Chemotherapy-naïve stage IIIB (wet) or IV NSCLC N=99 Carboplatin + Paclitaxel Placebo Carboplatin + Paclitaxel Bevacizumab 7.5 mg/kg PD Bevacizumab 15 mg/kg PD=progressive disease. Carboplatin + Paclitaxel Bevacizumab 15 mg/kg Johnson. J Clin Oncol. 2004;22:2184; Sandler. ASCO. 2005 (abstr 4).

Reason #2: Cisplatin/Pemetrexed vs Cisplatin/ Gemcitabine in Advanced NSCLC: Results Nonsquamous Squamous Survival Probability Median Survival 11.8 mos 10.4 mos CP vs CG Adjusted HR 0.81;0.70, 0.94 0.81 Survival Probability CP vs CG Median Survival 9.4;8.4, 9.4 10.2 mos 10.8;9.5, 12.1 10.8 mos Adjusted HR 1.23 1.23;1.00, 1.51 Survival Time (months) in Patients With Nonsquamous Histology Survival Time (months) in Patients With SCC Scagliotti GV et al: J Clin Oncol. 26 (21), 2008: 3543-3551.

Reason #3 Molecular Testing

Molecular Profiling and Therapeutic Decision Making for Advanced NSCLC General Guidelines for 2013 Who to test: patients with NSCLC and adenocarcinoma component What to test for: EGFR mutation and ALK fusion (+ others?) When to test: at the time of diagnosis (not just when treatment decision needed) What specimen: core needle biopsy (or multi-pass FNA), cytology cell block, surgical biopsy (bone biopsy problematic) How to test: concurrently (not sequentially test-by-test) How long a turnaround time is acceptable?: 2 weeks or less When to re-test: after a targeted therapy intervention (to assess for tumor evolution in the molecular profile) Adapted from: CAP/IASLC/AMP Guidelines

Reason #4: ORR by Histology: CbP vs Cb-nab-P in Advanced NSCLC a 95% CIs for response rate ratios are calculated according to the asymptotic 95% CI of the relative risk of nab-pc to sb-pc. Socinski MA et al, Annals of Oncology, 24:2390-6, 2013

Reason #5: SQUIRE Primary Outcome: Overall Survival ITT 1 Necitumumab + Cis/Gem Vs Cis/Gem Alone in Stage IV Squamous Carcinoma 100 80 GC+N N=545 GC N=548 Overall Survival (%) 60 40 20 GC+N GC Stratified HR (95% CI) 0.84 (0.74, 0.96) Stratified p-value (log-rank) 0.01 Median, months (95% CI) 11.5 (10.4, 12.6) 9.9 (8.9, 11.1) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time Since Randomization (Months) 1 Thatcher N, et al. Lancet Oncol 2015;16(7):763-74

Why Do Medical Oncologists Care About Histology? Molecular testing Current guidelines recommend routine testing for EGFR and ALK in adenocarcinoma Therapeutic considerations Bevacizumab contraindicated in squamous histology due to risk of pulmonary hemorrhage Pemetrexed indicated in non-squamous histologies Nab-P + Cb has superior ORR in squamous histology Necitumumab indicated in squamous histology Prognosis In general, individuals with non squamous cell lung cancer do slightly better than those with squamous cell Lindeman et al, 2013, Scagliotti et al, 2008. Johnson et al, 2004. Thatcher et al, 2015