Chapter 3 Treatment guidelines for NSCLC that does not have targetable driver mutations

NCCN treatment guidelines for advanced, metastatic NSCLC Initial cytotoxic therapy: Albumin-bound paclitaxel Platinum-based doublets Docetaxel Gemcitabine Gemcitabine/docetaxel Gemcitabine/vinorelbine Paclitaxel Pemetrexed Initial cytotoxic therapy: Bevacizumab/carboplatin/paclitaxel (Category 1)*§¶ Bevacizumab/carboplatin/pemetrexed*§¶ Bevacizumab/cisplatin/pemetrexed*§¶ Platinum-based doublets (Category 1) Gemcitabine/docetaxel (Category 1) Gemcitabine/vinorelbine (Category 1) Pembrolizumab/carboplatin/pemetrexed (Category 1)** Pembrolizumab/cisplatin/pemetrexed (Category 1)** Atezolizumab/carboplatin/paclitaxel/bevacizumab (Category 1) Subsequent therapy: Systemic immune checkpoint inhibitors (preferred) Nivolumab (Category 1)** or pembrolizumab (Category 1)**§§ or atezolizumab (Category 1)** or Other systemic therapy: Docetaxel or pemetrexed or gemcitabine or ramucirumab + docetaxel PS 0–2 Progression¶¶ Progression No EGFR or BRAF V600E mutations or ALK/ROS1 rearrangements, and PD-L1 expression negative (unless after progression with first-line pembrolizumab) PS 2 Tumour response evaluation after 2 cycles PS 3–4 BSC PS 0–1 Response or SD 4–6 cycles (total) Tumour response evaluation Adenocarcinoma*** Progression PS 3–4 BSC Continuation maintenance: Bevacizumab (Category 1) Pemetrexed (Category 1) Bevacizumab + pemetrexed (Category 1)§§§ Atezolizumab and/or bevacizumab (Category 1)¶¶¶ Gemcitabine (Category 2B) or Switch maintenance: Pemetrexed or Close observation Response or SD PD-L1 expression positive (≥50%) and EGFR, ALK, ROS1, BRAF negative or unknown Progression Pembrolizumab (Category 1) *Bevacizumab should be given until progression; §Any regimen with a high risk of thrombocytopenia and the potential risk of bleeding should be used with caution in combination with bevacizumab; ¶Criteria for treatment with bevacizumab: non-squamous NSCLC, and no recent history of haemoptysis. Bevacizumab should not be given as a single agent, unless as maintenance if initially used with chemotherapy; **If pembrolizumab not previously given; §§Pembrolizumab is approved for patients with NSCLC tumours with PD-L1 expression levels ≥1%, as determined by an FDA-approved test; ¶¶If not already given, options for PS 0–2 include (nivolumab, pembrolizumab, or atezolizumab), docetaxel (Category 2B), pemetrexed (Category 2B), gemcitabine (Category 2B), or ramucirumab + docetaxel (Category 2B); options for PS 3–4 include best supportive care. Options for further progression are best supportive care or clinical trial; ***All recommendations are Category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged; §§§If bevacizumab was used with a first-line pemetrexed/platinum chemotherapy regimen; ¶¶¶If atezolizumab/carboplatin/paclitaxel/bevacizumab given. ALK, anaplastic lymphoma kinase; BSC, best supportive care; EGFR, epidermal growth factor receptor; FDA, US Food and Drug Administration; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand 1; PS, performance status; SD, stable disease. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK). 1. National Comprehensive Cancer Network. NCCN Guidelines: Non-small Cell Lung Cancer Version 5. 2018. https://www.nccn.org/. Accessed: 05 October 2018.

ESMO treatment guidelines for advanced, metastatic NSCLC* Treatment should take into account histology, molecular pathology, age, performance status, comorbidities and patient preference PS 3–4 BSC [II,B] PS 3–4 BSC 4–6 cycles: Carboplatin-based doublets: <70 years and PS 2 [II,A] ≥70 years and PS 0–2 [I,A] Single-agent chemotherapy: Gemcitabine, vinorelbine, docetaxel [I,B] or pemetrexed [III,B] <70 years and PS 2 or Selected ≥70 years and PS 0–2 Disease progression Nivolumab [I,A; MCBS 5] Atezolizumab [I,A; MCBS 5] Pembrolizumab if PD-L1 >1% [I,A; MCBS 5] Docetaxel [I,B] Pemetrexed [I,B] Ramucirumab/docetaxel [I,B; MCBS 1] Nintedanib/docetaxel [II,B] Erlotinib [II,C] Stage IV NSCLC: Molecular tests negative (ALK/BRAF/ EGFR/ROS1) PS 0–2 Any expression of PD-L1§ 4–6 cycles: Cisplatin or carboplatin based doublets: (gemcitabine, docetaxel, paclitaxel, vinorelbine) [I,A] Cisplatin/pemetrexed [II,A] Carboplatin/pemetrexed [II,B] nab-PC [I,B] ± bevacizumab [I,A with carboplatin/paclitaxel, otherwise III,B] Maintenance treatment: Pemetrexed (continuation) [I,A] Gemcitabine (continuation) [I,B] Pemetrexed (switch) [I,B] ± bevacizumab (if given before) PR or SD Atezolizumab/bevacizumab with carboplatin and paclitaxel (4–6 cycles), followed by atezolizumab/bevacizumab [I,A]¶ PS 0–1 Atezolizumab/pemetrexed/platinum-based chemotherapy (4–6 cycles), followed by atezolizumab [I,B]¶ PD-L1 ≥50% PS 0–1 Pembrolizumab [I,A; MCBS 5] Pembrolizumab/pemetrexed and platinum-based hemotherapy 4 cycles), followed by pembrolizumab [I,A; MCBS 4]¶ PS 0–1 Platinum-based chemotherapy (see first-line treatment without IO) High TMB (≥10 mutations/Mb) Disease progression Nivolumab/ipilimumab [I,A]¶ *Latest version of the guidelines published in 2018; §In absence of contraindications and conditioned by the registration and accessibility of anti-PD-(L)1 combinations with platinum-based chemotherapy, this strategy will be preferred to platinum-based chemotherapy in patients with PS 0–1 and PD-L1 <50%. Alternatively, if TMB can accurately be evaluated, and conditioned by the registration and accessibility, nivolumab plus ipilimumab should be preferred to platinum-based standard chemotherapy in patients with NSCLC with a high TMB; ¶not EMA-approved. BSC, best supportive care; EMA, European Medicine Agency; ESMO, European Society for Medical Oncology; IO, immuno-oncology; Mb, megabase; MCBS, ESMO-Magnitude of Clinical Benefit Scale; nab-PC, albumin-bound paclitaxel and carboplatin; NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand 1; PR, partial response; PS, performance status; SD, stable disease, TMB, tumour mutation burden. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK). 1. Planchard D, et al. Ann Oncol 2018;29(Suppl. 4):iv192–iv237.