NSCLC, non-small cell lung cancer.

1. NSCLC treatment guidelines:National Comprehensive Cancer Network and European Society for Medical Oncology NSCLC, non-small cell lung cancer.

2. National Comprehensive Cancer Network guidelines: BRAFV600E mutation+, ALK translocation+,ROS1translocation+ advanced or metastatic adenocarcinoma1 *For PS 0–4; §Beware of flare phenomenon in subset of patients who discontinue ALK inhibitor. If disease flare occurs, restart ALK inhibitor; ¶Patients who are intolerant to crizotinib may be switched to ceritinib, alectinib, or brigatinib; **If not previously given; §§Ceritinib, alectinib, or brigatinib are treatment options for patients with ALK-positive metastatic NSCLC that has progressed on crizotinib; ¶¶Lorlatinib is a treatment option after progression on crizotinib and alectinib, brigatinib, or ceritinib; ***Single-agent vemurafenib or dabrafenib are treatment options if the combination of dabrafenib + trametinib is not tolerated; ¶¶¶Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in patients who have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite premedication, or for patients where the standard premedications (i.e. dexamethasone, H2 blockers, H1 blockers) are contraindicated; §§§Carboplatin-based regimens are often used for patients with comorbidities or those who cannot tolerate cisplatin; ****Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents or presence of an oncogene, which would predict lack of benefit; §§§§If progression on PD-1/PD-L1 inhibitor, switching to another PD-1/PD-L1 inhibitor is not routinely recommended; ¶¶¶¶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 1. National Comprehensive Cancer Network. NCCN Guidelines: Non-small Cell Lung Cancer Version 3. 2019. https://www.nccn.org/ (Accessed: 18 December 2018).

3. National Comprehensive Cancer Network guidelines: EGFR mutation+ advanced or metastatic adenocarcinoma1 All recommendations are category 2A unless otherwise indicated. *For PS 0–4; §Beware of flare phenomenon in subset of patients who discontinue EGFR TKI. If disease flare occurs, restart EGFR TKI; ¶Afatinib + cetuximab may be considered in patients with disease progression on EGFR TKI therapy; **The data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR+/ALK+ NSCLC; §§Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in patients who have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite premedication, or for patients where the standard premedications(i.e. dexamethasone, H2 blockers, H1 blockers) are contraindicated; ¶¶Carboplatin-based regimens are often used for patients with comorbidities or those who cannot tolerate cisplatin; ***Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents or presence of an oncogene, which would predict lack of benefit; §§§If progression on PD-1/PD-L1 inhibitor, switching to another PD-1/PD-L1 inhibitor is not routinely recommended; ¶¶¶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; ¶¶¶¶Plasma-based testing should be considered at progression on EGFR TKIs for the T790M mutation. If plasma-based testing is negative, tissue-based testing with rebiopsy material is strongly recommended. Practitioners may want to consider scheduling the biopsy concurrently with plasma testing referral; *****Consider osimertinib (regardless of T790M status) or pulse erlotinib for progressive leptomeningeal disease; §§§§§In the randomised Phase III trial of dacomitinib, patients with brain metastases were not eligible for enrollment. In the setting of brain metastases, consider other options; ¶¶¶¶¶Beware of flare phenomenon in subset of patients who discontinue EGFR TKI. If disease flare occurs, restart EGFR TKI. 1. National Comprehensive Cancer Network. NCCN Guidelines: Non-small Cell Lung Cancer Version 3. 2019. https://www.nccn.org/ (Accessed: 18 December 2018).

4. National Comprehensive Cancer Network guidelines: non-targetable advanced or metastatic adenocarcioma1 All recommendations are category 2A unless otherwise indicated. *Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents or presence of an oncogene, which would predict lack of benefit; §If progression on PD-1/PD-L1 inhibitor, switching to another PD-1/PD-L1 inhibitor is not routinely recommended; ¶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; ¶¶The data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR+/ALK+ NSCLC; ***If progression on PD-1/PD-LI inhibitor, switching to another PD-1/PD-L1 inhibitor is not routinely recommended; §§§Pembrolizumab is approved for patients with NSCLC tumours with PD-L1 expression levels ≥1%, as determined by an FDA-approved test; ¶¶¶If not previously given; ****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 BSC. Options for further progression are BSC or clinical trial;. 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 patient has not received platinum-doublet chemotherapy, refer to systemic therapy. If patient received platinum chemotherapy and anti-PD-1/PD-L1, refer to subsequent therapy; *****If pembrolizumab monotherapy given; §§§§§If pembrolizumab/carboplatin/pemetrexed or pembrolizumab/cisplatin/pemetrexed given; ¶¶¶¶¶If atezolizumab/carboplatin/paclitaxel/bevacizumab given; ******If bevacizumab was used with a first-line pemetrexed/platinum chemotherapy regimen. 1. National Comprehensive Cancer Network. NCCN Guidelines: Non-small Cell Lung Cancer Version 3. 2019. https://www.nccn.org/ (Accessed: 18 December 2018).

5. National Comprehensive Cancer Network guidelines: advanced or metastatic squamous cell carcinoma1 *Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents or presence of an oncogene, which would predict lack of benefit; §If progression on PD-1/PD-L1 inhibitor, switching to another PD-1/PD-L1 inhibitor is not routinely recommended; ¶The data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR+/ALK+ NSCLC; **Pembrolizumab is approved for patients with NSCLC tumours with PD-L1 expression levels ≥1%, as determined by an FDA-approved test; §§If not previously given; ¶¶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 BSC. Options for further progression are BSC or clinical trial; ***If pembrolizumab monotherapy given; §§§If patient has not received platinum-doublet chemotherapy, refer to systemic therapy. If patient received platinum chemotherapy and anti-PD-1/PD-L1, refer to subsequent therapy; ¶¶¶ If pembrolizumab/(cisplatin or carboplatin)/(paclitaxel or albumin-bound paclitaxel) given. 1. National Comprehensive Cancer Network. NCCN Guidelines: Non-small Cell Lung Cancer Version 3. 2019. https://www.nccn.org/ (Accessed: 18 December 2018).

6. European Society for Medical Oncology guidelines: targetable advanced or metastatic NSCC1 Treatment strategy should take into account histology, molecular pathology, age, PS, comorbidities and patient preference *Not EMA-approved. §MCBS score for the combination of bevacizumab with gefitinib or erlotinib.¶PS 0–1: 4–6 cycles cisplatin or carboplatin based doublets (gemcitabine, docetaxel, paclitaxel, vinorelbine), cisplatin/pemetrexed, carboplatin/pemetrexed; carboplatin/nab-PC, ± bevacizumab; PS 2, <70 years and PS 0–2, selected ≥70 years: 4–6 cycles carboplatin-based chemotherapy, single-agent chemotherapy (gemcitabine, vinorelbine, docetaxel, pemetrexed). 1. Planchard D, et al. Ann Oncol2018;29(Suppl. 4):iv192–iv237 [Published online 3 October 2018; updated 26 January 2019].

7. European Society for Medical Oncology guidelines: non-targetable advanced or metastatic NSCC1 Treatment strategy should take into account histology, molecular pathology, age, PS, comorbidities and patient preference *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. 1. Planchard D, et al. Ann Oncol 2018;29(Suppl. 4):iv192–iv237 [Published online 3 October 2018; updated 26 January 2019].

8. European Society for Medical Oncology guidelines: advanced or metastatic SCC1 Treatment strategy should take into account histology, molecular pathology, age, PS, comorbidities and patient preference *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; §Molecular testing is not recommended in SCC, except in those rare circumstances when SCC is found in a never-, long-time ex- or light-smoker (<15 pack-years); ¶Not EMA-approved. 1. Planchard D, et al. Ann Oncol2018;29(Suppl. 4):iv192–iv237 [Published online 3 October 2018; updated 26 January 2019].