Non-Small Cell Lung Cancer Treatment Regimens

Days 1-28: Osimertinib 80mg orally once daily.

Repeat cycle every 4 weeks.

If further progression, refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma

If further progression, refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma

See EGFR Exon 19 Deletion or L858R Mutations: Subsequent Therapy

Refer to Systemic Therapy for Advanced or Metastatic Disease – Subsequent

If further progression, refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma

Refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma

If further progression, refer to Systemic Therapy for Advanced or Metastatic Disease – Subsequent

If further progression, refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma

If further progression, refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma

If further progression, refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma

Refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma

If further progression, refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma or Systemic Therapy for Advanced or Metastatic Disease – Subsequent

Refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma or Systemic Therapy for Advanced or Metastatic Disease – Subsequent

Refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma or Systemic Therapy for Advanced or Metastatic Disease – Subsequent

Refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Squamous Cell Carcinoma or Systemic Therapy for Advanced or Metastatic Disease – Subsequent

Refer to Systemic Therapy for Advanced or Metastatic Disease – Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Subsequent

Refer to Systemic Options for Advanced or Metastatic Disease: Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Subsequent: Adenocarcinoma or Squamous Cell Carcinoma

See Systemic Options for Advanced or Metastatic Disease: Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Subsequent: Adenocarcinoma or Squamous Cell Carcinoma

See Systemic Options for Advanced or Metastatic Disease: Adenocarcinoma, Systemic Therapy for Advanced or Metastatic Disease – Subsequent: Adenocarcinoma or Squamous Cell Carcinoma

See Systemic Therapy for Advanced or Metastatic Disease

See Systemic Therapy for Advanced or Metastatic Disease – Maintenance, Systemic Therapy for Advanced or Metastatic Disease – Subsequent or Progression: Adenocarcinoma or Squamous Cell Carcinoma

Best supportive care.

Best supportive care.

Best supportive care.

Best Supportive Care

Best supportive care.

 • PS 0-2:Nivolumab, Pembrolizumab, or Atezolizumab, Docetaxel (Category 2B), Pemetrexed (Category 2B), Gemcitabine (Category 2B), Ramucirumab + Docetaxel (Category 2B), or Albumin-bound Paclitaxel (Category 2B)

 • PS 3-4: Best supportive care

 • Options for further progression are best supportive care or clinical trial

 • PS 0-2: Nivolumab, Pembrolizumab, or Atezolizumab, Docetaxel (Category 2B), Gemcitabine (Category 2B), Ramucirumab + Docetaxel (Category 2B), or Albumin-bound Paclitaxel (Category 2B)

 • PS 3-4: Best supportive care

 • Options for further progression are best supportive care or clinical trial.

All regimens can be used for sequential chemotherapy/RT

a  For performance status (PS) 0-4

b  For EGFR mutation discovered during first-line treatment, complete planned therapy, including maintenance therapy or interrupt, followed by Osimertinib (preferred) or Erlotinib or Afatinib or Dacomitinib, or Erlotinib + Ramucirumab or Erlotinib + Bevacizumab.

c  If systemic therapy regimen contains an immune checkpoint inhibitor, physicians should be aware of the long half-life of such drugs and data reporting adverse events when using osimertinib in combination with or following checkpoint inhibitors. Schoenfeld AJ, et al. Ann Oncol. 2019;30:839-844; Oshima Y, et al. JAMA Oncol. 2018;4:1112-1115. Oxnard GR, et al. Ann Oncol. 2020;31:507-516.

d  This agent may cause severe diarrhea. Evaluate risk of diarrhea prior to initiation of therapy, then monitor for episodes of diarrhea as clinically indicated for potential dose modification or discontinuation. Diarrhea may be treated with antidiarrheals (eg, loperamide). Patients may require IV hydration and electrolyte replacement.

e  This regimen may be associated with mucositis. Evaluate risk of mucositis prior to initiation of therapy, then monitor for episodes of mucositis as clinically indicated for potential dose modification or discontinuation. Patients may also require symptom management including topical mouthwashes, opioids for pain relief, IV hydration, and nutritional support.

f  An FDA-approved biosimilar is an appropriate substitute for Bevacizumab.

g  Criteria for treatment with Bevacizumab: non-squamous NSCLC, and no recent history of hemoptysis.

h  For Ramucirumab: Premedication for infusion reactions is required. The recommended dosing is: Diphenhydramine 12.5-50mg IV or orally 30 minutes pre-Ramucirumab.

I  Afatinib + Cetuximab (Days 1-14: Afatinib 40mg orally daily; Day 1: Cetuximab 500mg/m2 IV. Repeat cycle every 2 weeks.) (Janjigian YY, et al. Cancer Discov. 2014;4(9):1036-1045.)

J  If EGFR mutation discovered during first-line systemic therapy, complete planned systemic therapy, including maintenance therapy, or interrupt, followed by Afatinib (preferred) or Osimertinib (preferred) or Erlotinib or Gefitinib or Dacomitinib.

k  For Amivantamab-vmjw: Premedication for infusion reactions is required. The recommended dosing is:

• For first and second infusion: Methylprednisolone 40mg or dexamethasone 10mg IV 45-60 minutes pre-Amivantamab-vmjw. For subsequent infusions (if first and second tolerated): Methylprednisolone or Dexamethasone may be omitted AND

• Diphenhydramine 25-50mg IV or orally 15-60 minutes pre-Amivantamab-vmjw AND

• Acetaminophen 650-1,000mg IV or orally 15-60 minutes pre-Amivantamab-vmjw

l  This agent may cause severe diarrhea. Evaluate risk of diarrhea prior to initiation of therapy, then monitor for episodes of diarrhea as clinically indicated for potential dose modification or discontinuation. Diarrhea may be treated with antidiarrheals (eg, loperamide). Patients may require IV hydration and electrolyte replacement.

m  If ALK rearrangement discovered during first-line systemic therapy, complete planned systemic therapy, including maintenance therapy, or interrupt, followed by Alectinib (preferred) or Brigatinib (preferred) or Lorlatinib (preferred) or Ceritinib or Crizotinib

n  This agent may cause gastrointestinal toxicities, including both constipation and diarrhea. Evaluate risk prior to initiation of therapy. Patients may require prophylaxis or treatment of symptoms with a bowel regimen, antidiarrheals, intravenous hydration and/or electrolyte replacement. Monitor for symptoms as clinically indicated for potential dose modification or discontinuation.

o  If ROS1 rearrangement discovered during first-line systemic therapy, complete planned systemic therapy, including maintenance therapy, or interrupt, followed by Crizotinib (preferred) or Entrectinib (preferred) or Ceritinib.

p  If BRAF V600E mutation discovered during first-line systemic therapy, complete planned systemic therapy, including maintenance therapy, or interrupt, followed by dabrafenib + trametinib (preferred). Single-agent vemurafenib or dabrafenib are treatment options if the combination of dabrafenib + trametinib is not tolerated.

q  Antipyretic prophylaxis should be considered when clinically warranted. Review drug package insert for specific recommendations.

r  If NTRK1/2/3 gene fusion discovered during first-line systemic therapy, complete planned systemic therapy, including maintenance therapy, or interrupt, followed by Larotrectinib or Entrectinib.

s  If METex14 skipping mutation discovered during first-line systemic therapy, complete planned systemic therapy, including maintenance therapy, or interrupt, followed by Capmatinib (preferred) or Tepotinib (preferred) or Crizotinib.

t  If RET rearrangement discovered during first-line therapy, complete planned systemic therapy, including maintenance therapy, or interrupt, followed by Selpercatinib (preferred), Pralsetinib (preferred), Cabozantinib.

u  Early- and late-onset immune-related adverse events affecting multiple organ systems can occur in patients receiving immune checkpoint inhibitors. Patients with neurologic or life-threatening autoimmune disorders as well as receiving high levels of immunosuppression for their underlying disease should be approached with caution when considering immunotherapy. All patients will require extensive resources including ongoing intensive monitoring and supportive care.

v  For Pemetrexed: premedication and supplemental medications to reduce the incidence and severity of hematologic, gastrointestinal, and cutaneous toxicities are required. The recommended dosing is:

 • Vitamin B₁₂ (cyanocobalamin) 1,000mcg IM during the week preceding the first cycle of Pemetrexed and every 3 cycles thereafter AND

 • Folic acid 400-1000mcg orally daily starting 7 days before ethe first cycle and continuing for 21 days after the last dose of Pemetrexed AND

 • Dexamethasone 4mg orally twice daily for 3 days starting the day prior to Pemetrexed.

w  For Paclitaxel: premedication for hypersensitivity is required:

 • H₂ antagonist: Famotidine 20mg IV or orally (or equivalent H₂ blocker) 30-60 minutes pre-Paclitaxel AND

 • H₁ antagonist: Diphenhydramine 12.5-50mg IV or orally 30-60 minutes pre-Paclitaxel AND

• Dexamethasone 20mg orally approximately 12 and 6 hours pre-Paclitaxel OR Dexamethasone 20 mg IV 30 minutes pre-Paclitaxel

x  If Atezolizumab/Carboplatin/Albumin-bound Paclitaxel or Atezolizumab given (category 1 following Atezolizumab alone).

y  If Atezolizumab/Carboplatin/Paclitaxel/Bevacizumab given.

z  If Pembrolizumab monotherapy given.

aa  If Pembrolizumab/Carboplatin/Pemetrexed or Pembrolizumab/Cisplatin/Pemetrexed given.

bb  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”.

cc  If Pembrolizumab/Carboplatin/(Paclitaxel or Albumin-bound Paclitaxel) given.

dd  Hydration is required with supplemental electrolytes pre- and post-administration of Cisplatin.

ee  If Nivolumab + Ipilimumab ± chemotherapy given.

ff  If progression on PD-1/PD-L1 inhibitor, using a PD-1/PD-L1 inhibitor is not recommended.

gg  Bevacizumab should be given until progression.

hh For Docetaxel, premedication with Dexamethasone for fluid retention is required. One recommended dosing strategy is:

• Dexamethasone 8 mg orally twice daily for three consecutive days start 1 day prior to Docetaxel administration.

ii  If Bevacizumab was used with a first-line Pemetrexed/platinum chemotherapy regimen.

jj  Osimertinib for patients with completely resected stage IB-IIIA EGFR (exon 19 deletion; L858R) NSCLC who received previous adjuvant chemotherapy or are ineligible to receive platinum-based chemotherapy.

kk  Nivolumab in combination with platinum-based chemotherapy can be used for patients with resectable (tumors ≥4 cm or node positive) NSCLC in the neoadjuvant setting. If an immune checkpoint inhibitor is used in the pre-operative setting, an immune checkpoint inhibitor should not be used in the adjuvant setting.

ll  For patients with superior sulcus tumors, the recommendation is for 2 cycles concurrent with radiation therapy and 2 more after surgery.

mm  Regimens can be used as preoperative/adjuvant chemotherapy/radiotherapy.

nn  Regimens can be used as definitive concurrent chemotherapy/radiotherapy.

oo  For eligible patients, Durvalumab may be used after noted concurrent chemo/radiotherapy regimens.

pp  If using Durvalumab, an additional 2 cycles of chemotherapy is not recommended.

 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Non-small cell lung cancer VV3.2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed March 16, 2022.

 2. Osimertinib (Tagrisso) [package insert]. Wilmington, DE: AztraZeneca Pharmaceuticals; 2019.

 3. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629-640.

 4. Ramalingam SS, Yang JC, Lee CK, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol. 2018;36:841-849.

 5. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non small-cell lung cancer. N Engl J Med. 2018;378:113-125.

 6. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723.

 7. Afatinib (Gilotrif) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; November 2019.

 8. Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16:141-151.

 9. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334.

10. Dacomitinib (Vizimpro) [package insert]. New York, NY: Pfizer, Inc.; November 2020.

11. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:1454-1466.

12. Erlotinib (Tarceva) [package insert]. South San Francisco, CA: Genentech Inc. 2016.

13. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-132.

14. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo- controlled phase 3 study. Lancet Oncol. 2010;11:521-529.

15. Pérol M, Chouaid C, Pérol D, et al. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-celeval lung cancer. J Clin Oncol. 2012;30:3516-3524.

16. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small cell lung cancer (EURTAC): a multicenter, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239-246.

17. Paik PK, Varghese AM, Sima CS, et al. Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component. Mol Cancer Ther. 2012;11:2535-2540.

18. Bevacizumab (Avastin) [package insert]. South San Francisco, CA: Genentech, Inc.; January 2021.

19. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019;20(5):625-635.

20. Ramucirumab (Cyramza) [package insert]. Indianapolis, IN: Eli Lilly and Co.; May 2020.

21. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:1655-1669.

22. Gefitinib (Iressa) [package insert]. Wilmington, DE: AztraZeneca Pharmaceuticals; May 2020.

23. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-2388.

24. Doullaird J-Y, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR mutation- positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014;110:55-62.

25. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957.

26. Amivantamab-vmjw (Rybrevant) [package insert]. Horsham, PA: Janssen Biotech, Inc.; December 2021.

27. Sabari JK, Shu CA, Park K, et al. Amivantamab in post-platinum EGFR exon 20 insertion mutant non-small cell lung cancer. J Thorac Oncol. 2021;16(3):S108-109.

28. Mobocertinib (Exkivity) [package insert]. Lexington, MA: Takeda Pharmaceuticals America, Inc.; September 2021.

29. Ramalingam SS, Zhou C, Kim TM, et al. Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study. J Clin Oncol. 2021;39:15_suppl, 9014-9014.

30. Sotorasib (Lumakras) [package insert]. Thousand Oaks, CA: Amgen Inc.; May 2021.

31. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371-2381.

32. Alectinib (Alecensa) [package insert]. South San Francisco, CA: Genentech Inc.; September 2021.

33. Ou SH, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: A phase II global study. J Clin Oncol. 2016;34:661-668.

34. Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small cell lung cancer: a single-group, multicenter, phase 2 trial. Lancet Oncol. 2016;17:234-242.

35. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377:829-838.

36. Brigatinib (Alunbrig) [package insert]. Cambridge, MA: Takeda Pharmaceuticals America, Inc.; 2021.

37. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018;379:2027-2039.

38. Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: A Randomized, multicenter phase II trial. J Clin Oncol. 2017;35:2490-2498.

39. Lorlatinib (Lorbrena) [package insert]. New York, NY: Pfizer, Inc.; January 2021.

40. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19:1654-1667.

41. Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029.

42. Shaw AT, Solomon BJ, Besse B, et al. ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer. J Clin Oncol. 2019;37(16):1370-1379.

43. Ceritinib (Zakadia) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; October 2021.

44. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189-1197.

45. Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389:917-929.

46. Lim SM, Kim HR, Lee JS, et al. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol. 2017;35:2613-2618.

47. Cho BC, Kim DW, Bearz A, et al. ASCEND-8: A Randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC). J Thorac Oncol. 2017;12:1357-1367.

48. Crizotinib (Xalkori) [package insert]. New York, NY: Pfizer Inc.; January 2021.

49. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167-2177.

50. Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371:1963-1971.

51. Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020;26:47-51.

52. Entrectinib (Rozlytrek) [package insert]. South San Francisco, CA: Genentech Inc.; May 2021.

53. Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):261-270.

54. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282.

55. Dabrafenib (Tafinlar) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; January 2021.

56. Trametinib (Mekinist) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; December 2021.

57. Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18:1307-1316.

58. Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17:984-993.

59. Gautschi O, Milia J, Cabarrou B, et al. Targeted therapy for patients with BRAF- mutant lung cancer: Results from the European EURAF cohort. J Thorac Oncol. 2015;10:1451-1457.

60. Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF(V600E)- positive advanced non-small-cell lung cancer: a single-arm, multicentre, open- label, phase 2 trial. Lancet Oncol. 2016;17:642-650.

61. Vemurafenib (Zelboraf) [package insert]. South San Francisco, CA: Genentech, Inc.; May 2020.

62. Peters S, Michielin O, Zimmermann S. Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma. Clin Oncol. 2013;31:e341-e344.

63. Larotrectinib (Vitrakvi) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; March 2021.

64. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion- positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739.

65. Capmatinib (Tabrecta) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; January 2022.

66. Wolf J, Seto T, Han JY, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383(10):944-957.

67. Tepotinib (Tepmetko) [package insert]. Rockland, MA: EMD Serono, Inc.; 2021.

68. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931-943.

69. Pralsetinib (Gavreto) [package insert]. South San Francisco, CA: Genentech Inc.; February 2022.

70. Gainor JF, Curigliano G, Kim D-W, et al. Registrational dataset from the phase I/II ARROW trial of Pralsetinib (BLU-667) in patients (pts0 with advanced RET fusions non-small cell lung cancer (NSCLC. [abstract]. J Clin Oncol. 2020:38(suppl; abstr 9515).

71. Selpercatinib (Retevmo) [package insert]. Indianapolis, IN: Eli Lilly and Co.; January 2021.

72. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med. 2020;383(9):813-824.

73. Cabozantinib (Cabometyx) [package insert]. Alameda, CA: Exelixis, Inc.; November 2021.

74. Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013;3(6):630-635.

75. Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 201;17(12):1653-1660.

76. Atezolizumab (Tecentriq) [package insert]. South San Francisco, CA: Genentech, Inc: January 2022.

77. Spigel D, de Marinis F, Giaccone G, et al. Impower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC. Ann Oncol. 2019:30:v871-v934.

78. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med. 2020;383(14):1328-1339.

79. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255-265.

80. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837-1846.

81. Pembrolizumab (Keytruda) [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; February 2021.

82. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078-2092.

83. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17:1497-1508.

84. Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020;131:68-75.

85. Cemiplimab-rwlc (Libtayo) [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; February 2021.

86. Sezer A, Kilickap S, Gumus M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open- label, global, phase 3, randomised, controlled trial. Lancet. 2021;397(10274):592-604.

87. Garon EB, Hellmann MD, Rizvi NA, et al. Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol. 2019;37(28):2518-2527.

88. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833.

89. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830.

90. West H, McCleod M, Hussein M, et al Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:924-937.

91. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301.

92. Nivolumab (Opdivo) [package insert]. Princeton, NJ: Bristol-Myers Squibb, Inc.; March 2022.

93. Ipilimumab (Yervoy) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.; March 2022.

94. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198-211.

95. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381:2020-2031.

96. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379:2040-2051.

97. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2450.

98. Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013;31:4349-4357.

99. Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013;31:3004-3011.

100. Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012;30:2055-2062.

101. Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003;21:3016-3024.

102. Klastersky J, Sculier JP, Lacroix H, et al. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol. 1990;8:1556-1562.

103. Frasci G, Comella P, Panza N, et al. Carboplatin-oral etoposide personalized dosing in elderly non-small cell lung cancer patients. Gruppo Oncologico Cooperativo Sud-Italia. Eur J Cancer. 1998;34:1710-1714.

104. Danson S, Middleton MR, O’Byrne KJ, et al. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced non-small cell lung carcinoma. Cancer. 2003;98:542-553.

105. Ohe Y, Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol. 2007;18:317-323.

106. Strauss GM, Herndon JE, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008;26(31):5043-5051.

107. Scagliotti GV, Kortsik C, Daik GGG, et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: a multicenter randomized phase II trial. Clin Cancer Res. 2005;11:690-696.

108. Cardenal F, Lopez-Cabrerizo MP, Anton A, et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999;17(1):12-18.

109. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351-360.

110. Ohe Y, Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol. 2007;18(2):317-323.

111. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551.

112. Perol M, Chouaid C, Perot D, et al. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemicitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012;30:3516-3524.

113. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346;92-98.

114. Kreuter M, Vansteenkiste J, Fischer JR, et al. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013;24:986-992.

115. Pujol JL, Breton JL, Gervais R, et al. Gemcitabine-docetaxel versus cisplatin- vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol. 2005;16:602-610.

116. Tan EH, Szczesna A, Krzakowski M, et al. Randomized study of vinorelbine– gemcitabine versus vinorelbine–carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2005;49:233-240.

117. Green MR, Manikhas GM, Orlov S, et al. Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol. 2006;17(8):1263-1268.

118. Rizvi NA, Riely GJ, Azzoli CG, et al. Phase I/II trial of weekly intravenous 130-nm albumin-bound paclitaxel as initial chemotherapy in patients with stage IV non-small-cell lung cancer. J Clin Oncol. 2008;26(4):639-643.

119. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000;18(12):2354-2362.

120. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27(4):591-598.

121. Zatloukai P, Kanitz E, Magyar P, et al. Gemcitabine in locally advanced and metastatic non-small cell lung cancer: the Central European phase II study. Lung Cancer. 1998;22(3):243-250.

122. Sederholm C, Hillerdal G, Lamberg K, et al. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005;23(33):8380-8388.

123. Lilenbaum RC, Herndon JE, List MA, et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol. 2005;23(1):190-196.

124. Ceresoli GL, Gregorc V, Cordio S, et al. Phase II study of weekly paclitaxel as second-line therapy in patients with advanced non-small cell lung cancer. Lung Cancer. 2004;44(2):231-239.

125. Yasuda K, Igishi T, Kawasaki Y, et al. Phase II study of weekly paclitaxel in patients with non-small cell lung cancer who have failed previous treatments. Oncology. 2004;66(5):347-352.

126. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22(9):1589-1597.

127. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374(9699):1432-1440.

128. Govindan R, Bogart J, Stinchcombe T, et al. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol. 2011;29(23):3120-3125.

129. Brahmer J, Reckamp KL, Bass P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer N Engl J Med. 2015;373(2):123-135.

130. Long GV, Tykodi SS, Schneider JG, et al. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol. 2018;29(11):2208-2213.

131. Horn L, Spigel DR, Vokes EE, et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017;35(35):3924-3933.

132. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639.

133. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

134. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005;352(25):2589-2597.

135. Usami N, Yokoi K, Hasegawa Y, et al. Phase II study of carboplatin and gemcitabine as adjuvant chemotherapy in patients with completely resected non-small cell lung cancer: a report from the Central Japan Lung Study Group, CJLSG 0503 trial. Int J Clin Oncol. 2010;15(6):583-587.

136. Zhang L, Ou W, Liu Q, et al. Pemetrexed plus carboplatin as adjuvant chemotherapy in patients with curative resected non-squamous non-small cell lung cancer. Thorac Cancer. 2014;5:50-56.

137. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398:1344-1357.

138. Forde PM, Spicer J, Lu S, et al. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial [abstract]. Cancer Res. 2021;81:Abstract CT003.

139. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005;23:5883-5891.

140. Bradley JD, Paulus R, Romaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;15:187-199.

141. Albain KS, Crowley JJ, Turrisi AT, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol. 2002;20(16):3454-3460.

142. Liang J, Bi N, Wu S, et al. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017;28(4):777-783.

143. Senan S, Brade A, Wang L-H, et al. PROCLAIM: Randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy of locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016;34:953-962.

144. Choy H, Gerber DE, Bradley JD, et al. Concurrent pemetrexed and radiation therapy in the treatment of patients with inoperable stage III non-small cell lung cancer: a systematic review of completed and ongoing studies. Lung Cancer. 2015;87:232-240.

145. Durvalumab (Imfinzi) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals, LP: July 2021.

146. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377:1919-1929.

147. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379:2342-2350.

148. Baverel PG, Dubois VFS, Jin CY, et al. Population pharmacokinetics of durvalumab in cancer patients and association with longitudinal biomarkers of disease status. Clin Pharmacol Ther. 2018;103(4):631-642.

149. Le X, Paz-Ares LG, Van Meerbeeck J, et al. Tepotinib in patients with advanced non-small cell lung cancer (NSCLC) with MET amplification (METamp). [abstract] J Clin Oncol. 2021;39(suppl_15):Abstract 9021.

150. Ou SH, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol. 2011;6:942-946.

151. Camidge RD, Ou SH, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer. [abstract] J Clin Oncol. 2014;32(Suppl 5):Abstract 8001.

152. Ado-trastuzumab emtansine (Kadcyla) [package insert]. South San Francisco, CA: Genentech Inc. February 2022.

153. Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: results from a phase II basket trial. J Clin Oncol. 2018;36:2532-2537.

154. Fam-trastuzumab deruxtecan-nxki (Enhertu) [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc. January 2021.

155. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small cell lung cancer. N Engl J Med. 2022;386(3):241-251.