Advanced Stage Squamous NSCLC: Evolution and Increasing Complexity of the Therapeutic Landscape Understanding Options: When Should TKIs be Considered? David R. Gandara, MD University of California Davis Comprehensive Cancer Center
Disclosures Research grants AstraZeneca/Medimmune, Bristol-Myers Squibb, Clovis, Genentech, Johnson & Johnson, Eli Lilly, Merck, Novartis Consultant Ariad Pharmaceuticals, AstraZeneca, Bayer, Boehringer-Ingelheim, Celgene, Clovis, Genentech, Guardant Health, Eli Lilly, Liquid Genomics, Merck, Mirati, Novartis, Peregrine, Pfizer, Response Genetics, Synta Pharmaceuticals
Disclaimer Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF and in the US under the brand name GILOTRIF for use in patients with distinct types of EGFR mutation positive NSCLC. In Switzerland, GIOTRIF is indicated as monotherapy for the treatment of Epidermal Growth Factor Receptor (EGFR) TKI-naïve patients with stage IIIB/IV non-small cell lung cancer (NSCLC) with common activating EGFR mutation(s) (exon 19 deletions or exon 21 L858R substitution). The recommended dose is 40 mg once daily with no possibility for dose escalation. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in uncommon mutations and SqCC of the Lung and other indications in Switzerland.
Evolution in Therapeutic Landscape: A Compartmental Algorithm (2014) Patients with advanced stage NSCLC (PS 0 1) Oncogene-driven Non-squamous Non-oncogenedriven Squamous All First-line TKI (targeted therapy) therapy doublet +/ bev therapy doublet First-line maintenance EGFR mutation ALK translocation Pem or bev Or erlotinib therapy Or erlotinib Second-line therapy +/ TKI 2 nd -gen TKI therapy Or erlotinib therapy Or erlotinib Third-line therapy therapy therapy Or erlotinib Or erlotinib ALK, anaplastic lymphoma kinase; Bev, bevacizumab; EGFR, epidermal growth factor receptor; Gen, generation; NSCLC, non-small cell lung cancer; Pem, pemetrexed; PS, performance status; TKI, tyrosine kinase inhibitor. Adapted from Gandara DR, et al. Clin Lung Cancer. 2017;18:1 4.
Compartmental Treatment Algorithm: October 2016 1 st line Oncogene- Driven TKI (targeted therapy) EGFR, ALK, ROS1 Patients with Advanced NSCLC (PS 0-1) Non-squamous Squamous PD-L1+ PD-L1 PD-L1+ PD-L1 PD-1 doublet PD-1 doublet (± Neci ) 1 st line Maintenance TKIs PD-1 Pem/Bev PD-1 2 nd line 3 rd -gen TKIs EGFR/ALK Other TKIs PD-1/PD-L1 ( ± Ramu) PD-1/PD-L1 (± Ramu) PD-1/PD-L1 (+/- Ramu) PD-1/PD-L1 (+/- Ramu) 3 rd line doublet ALK, anaplastic lymphoma kinase; Bev, bevacizumab; EGFR, epidermal growth factor receptor; Gen, generation; NSCLC, non-small cell lung cancer; Pem, pemetrexed; PS, performance status; TKI, tyrosine kinase inhibitor. Adapted from Gandara DR, et al. Clin Lung Cancer. 2017;18:1 4. Or Afatinib Or Afatinib
Compartmental Treatment Algorithm: Squamous Lung Cancer Patients with Advanced NSCLC (PS 0 1) Squamous PD-L1+ PD-L1 First-line PD-1 doublet (+/- Neci ) First-line maintenance PD-1 PD-1/PD-L1 PD-1/PD-L1 Second-line (+/ ramu) (+/ ramu) Or afatinib (not suitable for immunotherapy) Third-line Or afatinib Or afatinib, chemotherapy; IOs, immuno-oncology therapies; Neci, necitumumab; NSCLC, non-small cell lung cancer; PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; PS, performance status; Ramu, ramucirumab;, negative; +, positive. Adapted from Gandara DR, et al. Clin Lung Cancer. 2017;18:1 4.
Patient Case: Advanced Recurrent SqCLC Presentation: 66-year-old woman with 50 pack per year smoking history presents with cough and fatigue (PS=1) At presentation Diagnosis: Stage IIIA NSCLC of squamous histology RUL peri-hilar mass with mediastinal LNs Mediastinoscopy positive for right levels R4 and 7 LNs MRI of brain negative LN, lymph nodes; MRI, magnetic resonance imaging; NSCLC, non-small cell lung cancer; PS, performance status; RUL, right upper lobe; RT, radiotherapy
Patient Case Continued Advanced, Recurrent SqCLC First-line treatment: Cisplatin-etoposide plus concurrent radiotherapy Relapse 18 months later in lung primary and bones (T2 shown) and adrenal glands; PS=1 At recurrence PS, performance status; SqCLC, squamous cell lung cancer.
Patient Case Continued Advanced, Recurrent SqCLC Question 1: In this patient with newly found SqCLC (Stage IV), would you test for PD-L1 in anticipation of possible PD-1/PD-L1-directed therapy? 1. Yes 2. No PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; SqCLC, squamous cell lung cancer.
Patient Case Continued Advanced, Recurrent SqCLC You decide to test for PD-L1 status by IHC assay Question 2: You have a variety of tests available to you through an outside CLIA-certified lab; which one of the following would you order? 1. 28-8 IHC assay (Dako) 2. 22C3 IHC assay (Dako) 3. SP263 IHC assay (Ventana) 4. SP142 (Ventana) CLIA, clinical laboratory improvement amendments; IHC, immunohistochemistry; PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; SqCLC, squamous cell lung cancer.
Patient Case Continued Advanced, Recurrent SqCLC PD-L1 testing by the Dako 22C3 IHC assay reveals a PD-L1 level of 55% Question 3: What treatment would you recommend for this patient who has a Zubrod performance score of 1? 1. You do not recommend immunotherapy at this particular time 2. Pembrolizumab based on PD-L1 >50% 3. Nivolumab regardless of PD-L1 level 4. Nivolumab based on PD-L1 >50% 5. Atezolizumab regardless of PD-L1 level IHC, immunohistochemistry; PD-L1, programmed death ligand 1; SqCLC, squamous cell lung cancer.
Patient Case Continued Advanced, Recurrent SqCLC The patient receives nivolumab and has a partial response that is maintained for 6 months (see scan) At that time, she develops progressive disease in multiple sites, including chest wall mass and worsening bone metastases (PS=1) In this patient who initially received platinum-based chemotherapy and then secondline immunotherapy, you decide to initiate third-line therapy IV, intravenous; SqCLC, squamous cell lung cancer.
Patient Case Continued Advanced, Recurrent SqCLC Question 4: Which of the available therapeutic options for advanced SqCLC would you employ? 1. Afatinib 2. Docetaxel + ramucirumab 3. Docetaxel alone PD-1, programmed cell death 1; PS, performance status; SqCLC, squamous cell lung cancer.
Patient Case Continued Advanced, Recurrent SqCLC You decide to treat with afatinib Question 5: Which of the following tests have proven useful in predicting the benefit of afatinib in patients with SqCLC? 1. EGFR protein expression by IHC 2. EGFR gene copy number by FISH 3. EGFR viii mutation 4. No predictive biomarker is necessary prior to employing afatinib in advanced SqCLC EGFR, epidermal growth factor receptor; FISH, fluorescent in situ hybridization; IHC, immunohistochemistry; SqCLC, squamous cell lung cancer.
The Patient is Treated with Afatinib 40 mg/day After recurrent mild diarrhea the dose is reduced to 30 mg/day with good tolerability afterwards Bone pain is reduced and PS remains 1 Repeat PET/CT scan at 3 months is consistent with stable disease CT, computerized tomography; PET, positron emission tomography; PS, performance status.
Emerging Treatment Algorithm for First-line Therapy of Advanced SqCLC: 2017 PD-L1 50% PD-L1 <50% Pembrolizumab Gemcitabine/platinum or Paclitaxel/carboplatin or Nab-pac/carboplatin or Gemcitabine/platinum Necitumumab Nab-pac, nab-paclitaxel; PD-L1, programmed death ligand 1; SqCLC, squamous cell lung carcinoma. Adapted from Gandara DR, et al. Clin Lung Cancer. 2017;18:1 4.
Turning Advanced Squamous Cell Lung Cancer into a Chronic Disease Requisites to turn squamous cell lung cancer into a chronic disease: Multiple therapeutic options Based on individual patient characteristics: age, PS, co-morbidities Based on biomarker status (PD-L1) for immunotherapy in first-line treatment Multiple lines of therapy 1 st -line 2 nd -line 3 rd -line 4 th -line Which therapy to employ and when to do so is now individualized on a patient-by-patient basis (Precision Medicine) PD-L1, programmed death ligand 1; PS, performance status. Gandara DR, et al. Clin Cancer Res. 2015;21:2236 43.
KEYNOTE-024: Pembrolizumab Versus Platinum-Doublet therapy in First-line Treatment of Advanced NSCLC 1 2 Key eligibility criteria Untreated Stage IV NSCLC PD-L1 TPS 50% ECOG PS 0 1 No activating EGFR mutation or ALK translocation No untreated brain metastases No active autoimmune disease requiring systemic therapy R (1:1) N=305 Pembrolizumab 200 mg IV Q3W (2 years) Platinum-doublet chemotherapy (4 6 cycles) PD * Crossover to Pembrolizumab 200 mg Q3W for 2 years Key endpoints Primary: PFS (RECIST v1.1 per blinded, independent central review) Secondary: OS, ORR and safety Exploratory: DOR *To be eligible for crossover, PD had to be confirmed by blinded, independent central radiology review and all safety criteria had to be met. ALK, anaplastic lymphoma kinase; DOR, duration of response; ECOG PS, Eastern Cooperative Group performance status; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PD, disease progression; ORR, objective response rate; OS, overall survival; PFS, progression free survival; R, randomization; PD-L1, programmed death ligand 1; Q3W, every three weeks; TPS, tumor proportion score. 1. Reck M, et al. Ann Oncol 2016;27(suppl 6):abstract LBA08; 2. Reck M, et al. N Engl J Med. 2016;375:1823 33.
KEYNOTE-024: Pembrolizumab Versus Platinum-doublet therapy 1 2 PFS (primary endpoint) OS (secondary endpoint), chemotherapy; CI, confidence interval; HR, hazard ratio; mo, months; OS, overall survival; PFS, progression free survival; Pembo, pembrolizumab. 1. Reck M, et al. N Engl J Med. 2016;375:1823 33; 2. NICE Single Technology Appraisal committee papers [ID990].
Emerging Treatment Algorithm for Advanced SqCLC in 2017: Second-line and Beyond If 1 st -line immunotherapy given If 1 st -line chemotherapy given 2 nd -line options Gemcitabine/platinum or Gemcitabine/platinum + necitumumab or Paclitaxel/carboplatin or Nab-pac/carboplatin 3 rd -line options Afatinib or Docetaxel ± ramucirumab 2 nd -line options Nivolumab or pembrolizumab (PD-L1 1%) or atezolizumab Nab-pac, nab-paclitaxel; PD-L1, programmed death ligand 1; SqCLC, squamous cell lung cancer.
Phase III Trials of PD-1/PD-L1 therapy compared to Docetaxel in 2nd/3rd-Line Advanced/Metastatic NSCLC Nivolumab All comers Strategy: (PD-L1+ & PD-L1-) Pembrolizumab Marker positive Strategy: PD-L1+ Atezolizumab Marker positive Strategy: PD-L1+ (TC+ ITL) POSITIVE POSITIVE POSITIVE IV, intravenous; NSCLC, non-small cell lung cancer; OS, overall survival; PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; Pembro, pembrolizumab; Q2W, every 2 weeks; Q3W, every 3 weeks. 1. Brahmer J, et al. 2015. N Engl J Med; 373:123 35; 2. Borghaei H, et al. N Engl J Med. 2015;373:1627 39; 3. Herbst RS, et al. Lancet. 2016;387:1540 50; 4. Rittmeyer A, Gandara DR, et al. Lancet. 2017;389:255 65.
PFS (%) OS (%) LUX-Lung 8: Afatinib Versus Erlotinib in Lung SqCLC Primary endpoint: PFS Secondary endpoint: OS 100 80 60 40 20 Median PFS, months (95% CI) Afatinib (n=398) 2.6 (2.0 2.9) Erlotinib (n=397) 1.9 (1.9 2.1) HR (95% CI) 0.81 (0.69 0.96) P value P=0.0103 Afatinib Erlotinib 100 80 60 40 20 28.2% Median OS, months (95% CI) 36.4% 22.0% Afatinib (n=398) 7.9 (7.2 8.7) Erlotinib (n=397) 6.8 (5.9 7.8) HR (95% CI) 0.81 (0.69 0.95) P value P=0.0077 Afatinib Erlotinib 0 0 3 6 9 12 15 18 21 24 27 Months 0 0 14.4% 3 6 9 12 15 18 21 24 27 30 Objective response rate: 6% vs 3% (P=0.055) Disease control rate: 51% vs 40% (P=0.002) Soria JC, et al. Lancet Oncol. 2015;16:897 907. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; QD, daily; SqCLC, squamous cell lung cancer.
LUX-Lung 8: Overall Survival Subgroup Analysis Factors No. of Patients HR (95% CI) Overall 795 0.81 (0.69 0.95) Age <65 years 399 0.68 (0.55 0.85) 65 years 396 0.95 (0.76 1.19) Gender Male 666 0.82 (0.69 0.97) Female 129 0.77 (0.51 1.14) Race Non-East Asian 623 0.87 (0.73 1.03) East Asian 172 0.62 (0.44 0.88) ECOG at baseline 0 260 0.76 (0.51 1.01) 1 531 0.80 (0.66 0.97) Smoking history Never smoker 44 0.77 (0.37 1.57) Light ex-smoker 23 0.43 (0.16 1.12) Current and other ex-smoker 728 0.81 (0.69 0.96) Histology Squamous 763 0.82 (0.70 0.96) Mixed 32 0.55 (0.26 1.17) Best response to first-line chemotherapy CR/PR 371 0.91 (0.72 1.15) SD 328 0.71 (0.56 0.90) Unknown 89 0.72 (0.44 1.17) 1/16 1/4 1 4 16 Favors Afatinib Favors Erlotinib Soria JC, et al. Lancet Oncol. 2015;16:897 907. CI, confidence interval; CR, complete response; HR, hazard ratio; ECOG, Eastern Cooperative Oncology Group; PR, partial response; SD, stable disease.
LUX-Lung 8: Patient-reported Outcomes Symptom improvement Time to deterioration Afatinib Erlotinib Number of patients HR (95% Cl) Coughing (Q1 from QLQ-LC13) 35.2 43.4 p=0.03 Coughing (Q1 from QLQ-LC13) 793 0.89 (0.72 1.09) Dyspnea (Q3 Q5 from QLQ-LC13) 44.1 51.3 p=0.06 Dyspnea (Q3 Q5 from QLQ-LC13) 793 0.79 (0.66 0.94) Pain (Q9, Q19 from QLQ-C30 40.2 39.2 p=0.78 Pain (Q9, Q19 from QLQ-C30) 793 0.99 (0.82 1.18) GHS/QoL (Q29 Q30 from QLQ-C30) 28.3 35.7 p=0.04 GHS/QoL (Q29 Q30 from QLQ-C30) 793 0.93 (0.78 1.12) 0 10 20 30 40 50 60 1/4 1/2 1 2 4 Patients with improvement in symptoms (%) Favors afatinib Favors erlotinib GHS, global health status; QoL, quality of life. PRO analysis from LUX-Lung 8 reported in Gadgeel SM, et al; abstract 8100 (poster board 425) presented at ASCO 2015.
EGFR Tyrosine Kinase Inhibitors in SqCLC Hirsch FR, Gandara DR, et al. Lancet Oncol. 2015;16:872 3. EGFR, epidermal growth factor receptor; SqCLC, squamous cell lung carcinoma.
Faculty Discussion Chair Rolf Stahel University Hospital of Zürich, Switzerland David R. Gandara University of California Davis Cancer Center, USA Noemí Reguart Hospital Clínic de Barcelona, Spain Maximilian Hochmair Otto Wagner Spital, Vienna, Austria 26