Robert Pirker Medical University of Vienna Vienna, Austria The road less travelled: what options are available for patients with advanced squamous cell carcinoma?
Disclosures Honoraria for advisory board/consulting AstraZeneca Boehringer Ingelheim Clovis Eli Lilly Pfizer Roche Speaker s fee AstraZeneca Boehringer Ingelheim Eli Lilly Data safety monitoring board Merck Sharp & Dohme Genmab Regeneron Synta
Learning objective After this presentation, participants will be able to describe current and emerging treatment modalities (targeted, anti-angiogenesis, immunotherapy) for advanced squamous NSCLC summarize their efficacy and safety in recent clinical trials
Case discussion A 65-year-old male, former smoker Cough for 3 months, ECOG-1 Diagnosis: squamous cell carcinoma stage IV ECOG-1, Eastern Cooperative Oncology Group performance status score of 1. Courtesy of R. Pirker.
Case A (continued) Courtesy of R. Pirker.
Case A (continued) 65-year-old male, former smoker Cough for 3 months, ECOG-1 Diagnosis: squamous cell carcinoma stage IV Treatment? EGFR IHC score 200; PD-L1 5% EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; PD-L1, programmed death-ligand 1. Courtesy of R. Pirker.
Question 1 Which treatment would you start? 1. Cisplatin + gemcitabine 2. Cisplatin + gemcitabine + necitumumab 3. Platin + gemcitabine + bevacizumab 4. Pembrolizumab 5. Other
Metastatic NSCLC: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up 1 PD-L1 50% PS 0 1 2 Pembrolizumab 2 PS 1 < 70 years Squamous NSCLC (stage IV) No driver mutation PS 2 < 70 years or PS 0 2 > 70 years PS 3 4 4 6 cycles Platinum-based doublet a Necitumumab-cisplatingemcitabine if IHC EGFR +ve 4 6 cycles Carboplatin based doublet a Single agent (gemcitabine, vinorelbine, docetaxel) BSC a Cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/paclitaxel; carboplatin/nab-paclitaxel. PS, performance status. 1. Based on Novello S, et al. Ann Oncol. 2016;27(Suppl 5):v1-27. 2. Reck, M. et al. N Eng J Med. 2016;375:1823-33.
OS (%) Cisplatin/gemcitabine ± necitumumab: SQUIRE Overall survival (n = 1,093) 100 80 60 40 20 Number at risk Necitumumab + gemcitabine and cisplatin Necitumumab + gemcitabine and cisplatin Gemcitabine and cisplatin Censored patients Necitumumab* + gemcitabine and cisplatin (n = 545) HR: 0.84 (95% CI: 0.74 0.96); p = 0.01 Median survival 11.5 months versus 9.9 months, 1-year survival rate 48% versus 43% Gemcitabine and cisplatin (n = 548) Patients censored, n (%) 127 (23) 106 (19) Median OS, months (95% CI) 11.5 (10.4 12.6) 9.9 (8.9 11.1) Stratified p value (log-rank) 0.01 Stratified HR (95% CI) 0.84 (0.74 0.96) * 800 mg i.v. days 1 and 8 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 545 496 450 407 358 291 243 208 176 130 101 84 61 42 32 20 11 3 3 0 0 Gemcitabine and cisplatin 548 494 435 379 308 254 219 182 153 115 80 63 49 33 27 19 9 7 3 1 0 OS, overall survival. Reproduced from Thatcher N, et al. Lancet Oncol. 2015;16:763-74 2015, Elsevier Ltd. All rights reserved.
OS (%) Cisplatin/gemcitabine ± necitumumab: SQUIRE Overall survival (n = 935: subpopulation of patients with EGFR protein expression) 100 80 60 40 Median OS, months Necitumumab + gemcitabine cisplatin 11.7 Gemcitabine cisplatin 10.0 HR (95% CI), p value 0.79 (0.69 0.92), p = 0.002 20 0 Necitumumab + gemcitabine cisplatin Gemcitabine cisplatin 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) HR: 0.79 (95% CI: 0.69 0.92); p = 0.002 Median survival 11.7 months versus 10.0 months Reproduced from Paz-Ares L, et al. Ann Oncol. 2016;27:1573-9 2016, Oxford University Press.
Case discussion B 73-year-old female, never smoker Increasing dyspnoea at exertion during last two months; ECOG-1 CT scan CT, computerized tomography. Courtesy of R. Pirker.
Case B (continued) Courtesy of R. Pirker.
Case B (continued) 73-year-old female, never smoker Increasing dyspnoea at exertion during last two months; ECOG-1 CT scan: lesions in right & left lung, mediastinal lymph node, cervical lymph node Treatment? Bronchoscopy Diagnosis: squamous cell carcinoma of the lung stage IV, no driver mutation Courtesy of R. Pirker.
Question 2 Which treatment would you start? 1. Gemcitabine or vinorelbine 2. Carboplatin + gemcitabine, or carboplatin + vinorelbine 3. Carboplatin + paclitaxel 4. Pembrolizumab 5. Other
Lung cancer therapy in elderly patients: factors to be considered Patient-related factors age and life expectancy gender performance status co-morbidity, organ functions geriatric syndromes functional status convenience of administration side effects of drugs polypharmacy patient preference Tumour-related factors histological subtype molecular characteristics tumour stage tumour growth Costs, cost effectiveness value-based judgements Courtesy of R. Pirker.
First-line chemotherapy in elderly patients with advanced NSCLC phase 3 trials Vinorelbine > BSC (ELVIS) 1 Vinorelbine = gemcitabine = gemcitabine/vinorelbine (MILES) 2 Vinorelbine + gemcitabine > vinorelbine 3 Carboplatin + paclitaxel > vinorelbine or gemcitabine 4 Single agent ± cisplatin (MILES 3 and MILES 4) 5 BSC, best supportive care. 1. Gridelli C, et al. J Natl Cancer Inst.1999;91:66-72. 2. Gridelli C, et al. J Natl Cancer Inst. 2003;95:362-72. 3. Frasci G, et al. J Clin Oncol. 2000;13:2529-36. 4. Quoix E, et al. Lancet. 2011;378:1079-88. 5. Gridelli C, et al. J Clin Oncol. 2017;35 Suppl 15:abstract 9002.
Case B (continued) 73-year-old female, never smoker Increasing dyspnoea at exertion during last two months; ECOG-1 CT scan: lesions in right and left lung, mediastinal lymph node, cervical lymph node Chemotherapy (2 cycles of carboplatin + gemcitabine; 2 cycles of gemcitabine) resulted in symptom relief and radiological partial response haematotoxicity (leucopenia, anaemia) Bronchoscopy Diagnosis: squamous cell carcinoma of the lung stage IV Courtesy of R. Pirker.
Case B (continued) Before chemotherapy After chemotherapy Courtesy of R. Pirker.
Patients (%) Patients (%) Predicting chemotherapy toxicity in elderly patients Patients with lung (29%), GI (27%), gynaecologic (17%), breast (11%), GU (10%) or other (6%) cancers Toxicity grade 3 5 Predictive model based on age 72 hearing (fair or worse) haemoglobin < 11 (male) or < 10 g/dl (female) falls in last six months (one or more) creatinine clearance < 34 ml/min walking one block (limited, somewhat, or a lot) cytoxic drugs (dosing; number) taking medications (some help/unable) decreased social activity cancer type GI or GU Main toxicities 100 80 60 40 20 0 leucopenia, anaemia fatigue, infection, dehydration Low 32 25 Medium 50 54 High 89 77 0 3 4 5 6 7 8 9 10 1112 19 Total risk score 100 90 80 70 <70 MD-rated KPS (%) GI, gastrointestinal; GU, genitourinary; MD, physician; KPS, Karnofsky performance status. Hurria A, et al. J Clin Oncol. 2011;29:3457-65. 100 80 60 40 20 0 54 48 51 63 57
Chemotherapy in elderly patients with advanced NSCLC Individualized therapy based on evidence, personal experience (judgement), and patient preference Performance status, co-morbidity, organ function, geriatric syndromes, social support, life expectancy, patient preference Chemotherapy protocols for first-line therapy fit patients: doublet or single agent vulnerable patients: consider single agent frail patients: no chemotherapy Expect increased toxicity Enhanced supportive care prophylaxis of emesis, obstipation, infection, and dehydration Aged over 80: no general recommendations Courtesy of R. Pirker.
Case discussion C 50-year-old male, heavy smoker Pain in left shoulder for several weeks; ECOG-1 CT scan: lesions in left upper lung, suspicious lesion in right adrenal gland CT-guided biopsy of the left lung Diagnosis: squamous cell carcinoma of the left lung, stage IV (?) PD-L1 negative Chemotherapy plus thoracic radiotherapy Courtesy of R. Pirker.
Case C (continued) Before chemotherapy After chemotherapy Courtesy of R. Pirker.
Question 3 Progression after chemotherapy (cisplatin + vinorelbine) and radiotherapy: which treatment would you start? 1. Docetaxel 2. Docetaxel + ramucirumab 3. Immune checkpoint inhibitor 4. Afatinib 5. Other
Metastatic NSCLC: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up Progression after front-line treatment (SCC stage IV) PS 0 2 PS 3 4 Nivolumab Pembrolizumab if PD-L1 > 1% Docetaxel Docetaxel + ramucirumab Erlotinib Afatinib BSC SCC, squamous cell carcinoma. Based on Novello S, et al. Ann Oncol. 2016;27(Suppl 5):v1-27.
Recent advances in pre-treated patients with advanced squamous NSCLC Docetaxel + ramucirumab (REVEL) 1 Afatinib in squamous cell NSCLC (LUX-Lung 8) 2 Nivolumab 3 Pembrolizumab 4 Atezolizumab 5 1. Garon EB, et al. Lancet. 2014;384:665-73. 2. Soria JC, et al. Lancet Oncol. 2015;16:897-907. 3. Brahmer J, et al. N Eng J Med. 2015;373:123-35. 4. Herbst RS, et al. Lancet. 2016;387:1540-50. 5. Rittmeyer A, et al. Lancet. 2017;389:255-65.
OS (%) Docetaxel ± ramucirumab (10 mg/kg): REVEL 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Ramucirumab + docetaxel Placebo + docetaxel Censored 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Number at risk Ramucirumab + docetaxel 628 527 415 329 231 156 103 70 45 23 11 2 0 Placebo + docetaxel 625 501 386 306 197 129 86 56 36 23 9 0 0 OS: HR 0.86 (95% CI: 0.75 0.98), p = 0.023 Median (95% CI) Censoring rate (%) Ramucirumab + docetaxel 10.5 months (9.5 11.2) 31.8 Placebo + docetaxel 9.1 months (8.4 10.0) 27.0 Ramucirumab vs placebo, Stratified HR (95% CI), p value 0.86 (0.75 0.98), p = 0.023 Reproduced from Garon EB, et al. Lancet 2014;384:665-73 2014, Elsevier Ltd. All rights reserved.
OS (%) Afatinib versus erlotinib in squamous cell carcinoma of the lung: LUX-Lung 8 100 80 60 40 20 0 Afatinib Erlotinib Afatinib 3 6 9 12 15 18 21 24 27 30 Time (months) Number at risk Afatinib 316 249 170 124 82 47 28 10 4 0 Erlotinib 305 210 150 94 54 30 11 4 2 0 OS: HR 0.81 (95% CI: 0.69-0.95), p = 0.0077 Erlotinib Median OS, months (95% CI) 7.9 (7.2 8.7) 6.8 (5.9 7.8) Soria JC, et al. Lancet Oncol. 2015;16:897-907.
OS (% of patients) OS (% of patients) Nivolumab versus docetaxel in advanced NSCLC: overall survival 100 80 Nivolumab Docetaxel 100 80 Nivolumab Docetaxel 60 40 20 42 24 60 40 20 51 39 0 3 6 9 12 15 18 21 Time (months) Number at risk Nivolumab 113 86 69 52 31 15 7 Docetaxel 103 68 45 30 14 7 2 Squamous 1 HR 0.59 (95% CI: 0.44 0.79) p < 0.001 0 3 6 9 12 15 18 21 24 Time (months) Number at risk Nivolumab 232 194 169 146 123 62 32 9 Docetaxel 244 194 150 111 88 34 10 5 Adenocarcinoma 2 HR 0.73 (95% CI: 0.59 0.89) p = 0.002 1. Brahmer J, et al. N Eng J Med. 2015;373:123-35. 2. Borghaei H, et al. N Eng J Med. 2015;373:1627-39.
OS (%) OS (%) Pembrolizumab (2 or 10 mg/kg) versus docetaxel in advanced NSCLC: overall survival 100 90 80 70 60 50 40 30 20 10 0 0 5 10 15 20 25 Number at risk Pembrolizumab 2 mg/kg 139 110 51 20 3 0 Pembrolizumab 10 mg/kg 151 115 60 25 1 0 Docetaxel 152 90 38 19 1 0 100 90 80 70 60 50 40 30 20 10 0 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 0 5 10 15 20 25 Time (months) Number at risk Pembrolizumab 2 mg/kg 344 259 115 49 12 0 Pembrolizumab 10 mg/kg 346 255 124 56 6 0 Docetaxel 343 212 79 33 1 0 PD-L1 50% Pembrolizumab 10 mg/kg every 3 weeks: HR 0.50 (95% CI: 0.36 0.70); p < 0.0001 Pembrolizumab 2 mg/kg every 3 weeks: HR 0.54 (95% CI: 0.38 0.77); p = 0.0002 All patients Pembrolizumab 10 mg/kg every 3 weeks: HR 0.61 (95% CI: 0.49 0.75); p < 0.0001 Pembrolizumab 2 mg/kg every 3 weeks: HR 0.71 (95% CI: 0.58 0.88); p = 0.0008 Reproduced from Herbst RS, et al. Lancet. 2016;387:1540-50 2016, Elsevier Ltd. All rights reserved.
Conclusions Necitumumab added to first-line chemotherapy with cisplatin plus gemcitabine improves survival of patients with advanced squamous cell carcinoma of the lung Elderly patients benefit from first-line chemotherapy with single agents or well-tolerated doublets, but require enhanced supportive care measures Ramucirumab added to docetaxel improves survival of patients with advanced NSCLC who have previously been treated with chemotherapy
Relative risk Relative risk Benefits of stopping smoking: UK Million Women Study Death from any cause 4 Death from lung cancer 30 3 2 1 1.01 1.05 1.20 Current smokers Women who never smoked 1.56 25 20 15 10 5 1.6 1.8 3.3 Current smokers Women who never smoked 5.9 0 20 30 40 50 0 20 30 40 50 Age of former smokers at cessation (year) Age of former smokers at cessation (year) Jha P, Peto R. N Eng J Med. 2014;370:60-8.
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