Non-Small Cell Lung Cancer (NSCLC) Treatment Protocols

Updated: Apr 04, 2022

Author: Marvaretta M Stevenson, MD; Chief Editor: Nagla Abdel Karim, MD, PhD

Treatment Recommendations, Early or Localized Disease

Stage IB (> 4 cm tumor size) or II disease

Surgery is recommended for patients with stage I B (> 4 cm tumor size) or II non–small cell lung cancer [NSCLC]) and may provide the best possibility for a cure. Surgery (radiation therapy if the patient is not a surgical candidate), with or without adjuvant chemotherapy based on risk factors, for stages IB and II is generally appropriate.

Adjuvant chemotherapy after surgical resection provides an absolute increase in 5-y survival of approximately 5%[1] ; median 5-y overall survival rates range from 45-70%. No benefit has been shown for adjuvant chemotherapy after surgery for stage I disease; the benefit of adding adjuvant chemotherapy increases as disease stage increases.[1]

Stereotactic body radiotherapy (SBRT) may be used in early-stage NSCLC tumors that are smaller than 5 cm and without lymph node involvement. This has become a viable and effective option for patients with early-stage NSCLC who are not surgical candidates and in those with significant co-morbidities. Studies show high local control rates (approximately 90%) for these patients. However, the protocols for SBRT have varied among the published studies.

Neoadjuvant and adjuvant chemotherapy regimens for stage IB or II NSCLC

With chemotherapy for stage IB or II NSCLC, the goal is to complete four cycles. Acceptable adjuvant chemotherapy regimens include the following:

Cisplatin 50 mg/m2 IV on days 1 and 8 plusvinorelbine 25 mg/m2 IV on days 1, 8, 15, and 22 every 28 d[1, 2, 3, 4, 5, 6] or
Cisplatin 100 mg/m2 IV on day 1 plus vinorelbine 30 mg/m2 on days 1, 8, 15, and 22 every 28 d[1, 2, 3, 4, 5, 6] or
Cisplatin 75-80 mg/m2 IV on day 1 plus vinorelbine 25-30 mg/m2 IV on days 1 and 8 every 21 d[1, 2, 3, 4, 5, 6] or
Cisplatin 100 mg/m2 IV on day 1 plusetoposide 100 mg/m2 IV on days 1-3 every 28 d[1, 2, 3] or
Cisplatin 80 mg/m2 IV on days 1, 22, 43, and 64 plusvinblastine 4 mg/m2 IV on days 1, 8, 15, 22, and 29; then every 2 wk after day 43 until completion of cisplatin every 21 d[1, 2, 3] or
Cisplatin 75 mg/m2 IV on day 1 plusgemcitabine 1250 mg/m2 on days 1 and 8 every 21 d (preferred for squamous histologies)[7] or
Cisplatin 75 mg/m2 IV on day 1 plusdocetaxel 75 mg/m2 IV on day 1 every 21 d (preferred for squamous histologies)[8] or
Cisplatin 75 mg/m2 IV on day 1 pluspemetrexed 500 mg/m2 IV on day 1 every 21 d (preferred for nonsquamous histologies)[7]

With chemotherapy for stage IB (> 4 cm), II, IIIA NSCLC, the goal is to complete three cycles. Acceptable neoadjuvant chemotherapy regimens include the following[9] :

Nivolumab 360 mg IV q3Weeks, plus
Platinum-doublet chemotherapy q3Weeks for three cycles

Platinum-doublet chemotherapy consists of the following:

Paclitaxel 175-200 mg/m ² and carboplatin AUC 5 or 6 (any histology) or
Pemetrexed 500 mg/m ² and cisplatin 75 mg/m ² (non-squamous histology) or
Gemcitabine 1000-1250 mg/m ² and cisplatin 75 mg/m ² (squamous histology)

Patients with comorbidities or patients not able to tolerate cisplatin may alternatively use one of the following regimens for a goal of four cycles:

Carboplatin AUC 6 IV on day 1 pluspaclitaxel 200 mg/m2 IV on day 1 every 21 d[10, 11] (see the Carboplatin AUC Dose Calculation [Calvert formula] calculator)
Carboplatin AUC 5 IV on day 1 plus gemcitabine 1000 mg/m2 IV on day 1 and 8 every 21 d [12]
Carboplatin AUC 5 IV on day 1 and pemetrexed 500 mg/m2 IV on day 1 every 21 d (for non-squamous histologies) [13]

Consider the following in patients with completely resected stage IB-IIIA EGFR mutation–positive NSCLC in patients who received previous adjuvant chemotherapy or are ineligible to receive platinum-based chemotherapy:

Osimertinib 80 mg PO daily, until disease recurrence, or unacceptable toxicity, or for up to 3 years ^[7]
Atezolizumab 840mg IV q2Weeks, 1200 mg IV q3Weeks, or 1680 mg IV q4Weeks for up to 1 year (for completely resected IIB-IIIA or high-risk stage IIA PD-L1 ≥1% NSCLC in patients who previously received adjuvant chemotherapy. ^[7]

Treatment of Locally Advanced Disease

Stage IIIa or IIIb disease

Stage IIIa and IIIb disease are typically treated with a combination of chemotherapy and radiation if the patient is not a surgical candidate. Selected patients (predominantly those with stage IIIa) may be surgical candidates; these patients may receive chemotherapy alone or chemotherapy with radiation before surgical resection.

Chemotherapy and radiation therapy are preferably given concurrently, but in patients with poor performance status, these therapies may be given sequentially. The decision to treat a patient with concurrent chemoradiation rather than surgery, radiation, or chemotherapy individually should be made by a multidisciplinary tumor board (including a medical oncologist, radiation therapist, and thoracic surgeon).[7, 14, 15]

Concurrent chemotherapy/radiation therapy regimens

Acceptable chemotherapy regimens for use in concurrent chemotherapy/radiation therapy are as follows:

Cisplatin 50 mg/m2 IV on days 1, 8, 29, and 36 plus etoposide 50 mg/m2 IV on days 1-5 and days 29-33[16, 17, 18, 19, 20] or
Cisplatin 100 mg/m2 IV on days 1 and 29 plus vinblastine 5 mg/m2/weekly IV for 5 wk[7, 21] or
Carboplatin AUC 2 IV weekly for 7 wk plus paclitaxel 45 - 50 mg/m2 IV weekly for 7 wk; 3 wk later, it can be followed by two cycles of consolidation chemotherapy with carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m2 IV on day 1 every 21 wk[22, 23] or
Carboplatin AUC 5 IV on day 1 plus pemetrexed 500 mg/m2 IV on day 1 every 21 d for four cycles (for non-squamous histologies)[24] or
Cisplatin 75 mg/m2 IV on day 1 plus pemetrexed 500 mg/m2 IV on day 1 every 21 d for three cycles (for non-squamous histologies)[25]

Sequential chemotherapy/radiation therapy regimens

Acceptable chemotherapy regimens for use in sequential chemotherapy/radiation therapy are as follows:

Cisplatin 100 mg/m2 IV on days 1 and 29 plus vinblastine 5 mg/m2/weekly IV on days 1, 8, 15, 22, and 29, followed by radiation therapy[7, 21, 26, 27] or
Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m2 IV on day 1 every 21 d for two cycles, followed by radiation therapy[7, 22, 23]

Consolidation therapy

Following concurrent chemotherapy and radiation therapy, National Comprehensive Cancer Network guidelines recommend consolidation therapy with durvalumab for stage III disease.[7]

Durvalumab is given as follows for up to 12 months[28] :

Patients weighing ≥30 kg: 10 mg/kg IV q2wk or 1500 mg IV q4wk infused over 60 min
Patients weighing < 30 kg: 10 mg/kg IV q2wk infused over 60 min

Immunotherapy for patients who are not candidates for surgery or definitive chemoradiation

Pembrolizumab is indicated as first-line monotherapy for patients with stage III NSCLC, who are not candidates for surgical resection or definitive chemoradiation and whose tumor expresses programmed death ligand 1 (PD-L1) with a Tumor Proportion Score (TPS) ≥1%.[29]

Pembrolizumab 200 mg IV q3wk or 400 mg IV q6wk; continue until disease progression or unacceptable toxicity (for up to 24 mo)

First-Line Therapy, Metastatic (Stage IV) or Recurrent Disease

Stage IV or Recurrent Disease

Patients with metastatic disease (stage IV) or recurrent disease after primary therapy (eg, surgery and/or radiation) should be considered for palliative treatment in order to improve quality of life, palliate symptoms, and improve overall survival.[14, 7] These patients should undergo molecular testing for oncogenes and programmed death ligand 1 (PD-L1.

Factors to be considered in the treatment choice for these patients include:

Presence of an oncogene (eg, EGFR, ALK)
Tumor histology (squamous versus non-squamous)
Candidacy for immune checkpoint inhibitors (immunotherapy)
Performance status and co-morbidities

Patients with advanced or recurrent disease with actionable oncogenes should be considered for treatment with targeted therapy (see section below). Patients without an actionable genetic alteration should be treated with chemotherapy alone, chemotherapy with immunotherapy, or immunotherapy alone. Patients with poor performance status or co-morbidities can be considered for single-agent chemotherapy, immunotherapy, or (if they have an actionable oncogene) targeted therapy.

First-line treatment options if not a candidate for targeted therapy

First-line treatment options for patients who are not candidates for targeted therapy are listed below. Unless otherwise specified, the goal is to treat for four to six cycles.

Chemotherapy regimens, including platinum-based doublets, for non-squamous and squamous histologies, are as follows:

Cisplatin 75 mg/m2 IV on day 1 plus paclitaxel 175 mg/m2 IV on day 1 every 21 d[30, 31] or
Cisplatin 100 mg/m2 IV on day 1 plus gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 28 d[31] or
Cisplatin 60 mg/m2 IV on day 1 plus gemcitabine 1000 mg/m2 IV on days 1 and 8 every 21 d[32, 33] or
Cisplatin 75 mg/m2 IV on day 1 plus docetaxel 75 mg/m2 IV on day 1 every 21 d[8, 31] or
Carboplatin AUC 6 IV on day 1 plus paclitaxel 175-225 mg/m2 IV on day 1 every 21 d[31, 34] or
Carboplatin AUC 6 IV on day 1 plus paclitaxel 90 mg/m2 IV on days 1, 8, and 15 every 28 d[35, 36, 37] or
Paclitaxel protein bound 100 mg/m2 IV on days 1, 8, and 15 of every 21 d plus carboplatin AUC 6 IV on day 1[38] or
Carboplatin AUC 6 IV on day 1 plus docetaxel 75 mg/m2 IV on day 1 every 21 d[20] or
Carboplatin AUC 5 IV on day 1 plus gemcitabine 1250 mg/m2 IV on days 1 and 8 every 21 d[39, 40, 41] or
Cisplatin 100 mg/m2 IV on day 1 every 28 d plus vinorelbine 25 mg/m2 IV weekly[8] or
Cisplatin 40 mg/m2 IV on day 1 plus vinorelbine 25 mg/m2 IV on days 1 and 8 every 21 d[32] or
Carboplatin AUC 5 IV on day 1 plus vinorelbine 30 mg/m2 IV on days 1 and 8 every 21 d[42]

Combination immunotherapy for first-line treatment of metastatic NSCLC with PD-L1 tumor expression ≥1% is as follows[43] :

Nivolumab 3 mg/kg IV q2wk, plus
Ipilimumab 1 mg/kg IV q6wk
Continue until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression

First-line treatment of metastatic squamous NSCLC is as follows:

Paclitaxel protein bound 100 mg/m2 IV on days 1, 8, and 15 of every 21 d plus carboplatin AUC 6 IV on day 1 ^[38] or
Pembrolizumab 200 mg IV and carboplatin AUC 6 mg/mL/min on day 1 of each 21 d cycle for four cycles plus paclitaxel 200 mg/m ² on day 1 or nab-paclitaxel 100 mg/m ² on days 1, 8, and 15 of each 21 d cycle for four cycles ^[44]; alternative pembrolizumab dose is 400 mg q6wk ^[29]

Bevacizumab-based regimens for patients who meet eligibility requirements (non-squamous histology, treated brain metastases, no history of hemoptysis) are as follows:

Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 every 21 d (continue bevacizumab every 21 d after four to six cycles are completed; continue until disease progression)[45] or
Cisplatin 80 mg/m2 IV on day 1 plus gemcitabine 1250 mg/m2 IV on days 1 and 8 plus bevacizumab 7.5-15 mg/kg IV on day 1 every 21 d (continue bevacizumab every 21 d after four to six cycles are completed); continue until disease progression or
Docetaxel 75 mg/m2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 every 21 d until disease progression or 52 wk of therapy[15] or
Carboplatin AUC 6 IV on day 1 plus pemetrexed 500 mg/m2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 every 21 d, with pemetrexed and bevacizumab continued until disease progression (plus folate and vitamin B12 supplements, along with dexamethasone premedication for pemetrexed)[46]

Pemetrexed plus pembrolizumab plus platinum therapy regimens for initial treatment in patients with nonsquamous NSCLC without EGFR or ALK genomic tumor aberrations are as follows:[47]

Pembrolizumab 200 mg plus pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 IV on day 1 every 21 d for four cycles (plus folate and vitamin B12 supplements along with dexamethasone premedication for pemetrexed) or
Pembrolizumab 200 mg plus pemetrexed 500 mg/m2 plus carboplatin AUC 5 IV on day 1 every 21 d for four cycles (plus folate and vitamin B12 supplements along with dexamethasone premedication for pemetrexed)
Administer pemetrexed IV over 10 min after pembrolizumab and before platinum-based therapy
Alternative pembrolizumab dose is 400 mg IV q6wk
Following treatment with platinum-based therapy, continue pemetrexed with or without pembrolizumab until disease progression or unacceptable toxicity

Pemetrexed plus cisplatin for initial treatment in patients with nonsquamous NSCLC:

Pemetrexed 500 mg/m ² IV administered 10 minutes before cisplatin 75 mg/m2 IV on day 1 every 21 d for up to six cycles in the absence of disease progression or unacceptable toxicity

Pembrolizumab can be used as a single-agent first-line for tumors that express PD-L1 (Tumor Proportion Score [TPS] ≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, as follows:[48, 49]

Pembrolizumab 200 mg IV q3wk or 400 mg IV q6wk until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression

Pembrolizumab is also indicated in combination with pemetrexed and carboplatin for first-line treatment of patients with metastatic nonsquamous NSCLC irrespective of PD-L1 expression, as follows:[47]

Pembrolizumab 200 mg IV plus pemetrexed 500 mg/m ² plus carboplatin (AUC 5 mg/mL/min) IV on Day 1 of each 21-day cycle for four cycles, then pembrolizumab 200 mg IV q3wk until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression
Alternatively, pembrolizumab 400 mg IV q6wk plus pemetrexed 500 mg/m2 plus carboplatin (AUC 5 mg/mL/min) IV on Day 1 of each 21-day cycle for four cycles, then pembrolizumab 400 mg IV q6wk until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression

Treatment recommendations for patients with contraindications to carboplatin or cisplatin are as follows:

Gemcitabine 1100 mg/m2 IV on days 1 and 8 plus docetaxel 100 mg/m2 IV on day 8 every 21 d[50, 51] or
Gemcitabine 1000-1200 mg/m2 IV on days 1 and 8 plus vinorelbine 25-30 mg/m2 IV on days 1 and 8 every 21 d[42, 52, 53, 54]

Single-Agent Therapy

Single-agent therapy is a reasonable first-line option in patients with good performance status (ECOG score ≤2) disease or in the elderly; the goal is to complete four to six cycles. Systemic chemotherapy is not indicated for patients with poor performance status (ECOG 3-4), except for erlotinib in patients who are EGFR-mutation positive.[7]

Single-agent regimens include the following:

Paclitaxel 200 mg/m2 IV every 21 d[55, 56] or
Docetaxel 35 mg/m2 IV weekly for 3 wk every 4wk[51, 57, 58, 59] or
Docetaxel 75 mg/m2 IV every 21 d[57, 60, 61, 58] or
Gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 4 wk[62, 63] or
Gemcitabine 1250 mg/m2 IV on days 1 and 8 every 21 d[39, 52] or
Vinorelbine 25 mg/m2 IV weekly[64, 65] or
Vinorelbine 30 mg/m2 IV on days 1 and 8 every 21d[52, 66, 67] or
Pemetrexed 500 mg/m2 IV every 21d[68] (non-squamous histology)

PD-1/PD-L1 Inhibitors

Pembrolizumab is indicated as first-line monotherapy for patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 (TPS ≥1%) with no EGFR or ALK genomic tumor aberrations. Pembrolizumab is also indicated after platinum-containing chemotherapy for tumors that express PD-L1 (TPS ≥1%). Patients with EGFR or ALK aberrations should have disease progression on US Food and Drug Administration (FDA)–approved therapy for those aberrations before receiving pembrolizumab; dose as follows:[48, 69, 49]

Pembrolizumab 200 mg IV q3wk or 400 mg IV q6wk; continue until disease progression or unacceptable toxicity (for up to 24 mo)

Atezolizumab is indicated as first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥50% of tumor cells [TC ≥50%] or PD-L1–stained tumor-infiltrating immune cells [IC] covering ≥10% of the tumor area [IC ≥ 10%]), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations:

Atezolizumab 840 mg IV q2wk, 1200 mg IV q3wk, or 1680 mg IV q4wk until disease progression or unacceptable toxicity ^[70]

Cemiplimab has received accelerated FDA approval for first-line treatment of NSCLC in patients whose tumors have high PD-L1 expression [TPS ≥50%] with no EGFR, ROS-1, or ALK mutations:

Cemiplimab 350 mg IV q3wk until disease progression or unacceptable toxicity ^[71]

Second-Line Therapy, Metastatic or Recurrent Disease

Stage IV or Recurrent Disease

Second-line therapy is given for advanced or recurrent disease after disease progression following first-line therapy. Second-line regimens are as follows:

Nivolumab 240 mg IV q2wk or 480 mg q4wk over 30 min; continue until disease progression or unacceptable toxicity[72] or
Pembrolizumab 200 mg IV q3wk until disease progression or unacceptable toxicity (for up to 24 mo) in tumors that are programmed death ligand 1 (PD-L1) positive; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab[69] ; alternative pembrolizumab dose is 400 mg IV q6wk or
Docetaxel 75 mg/m2 IV on day 1 every 21 d (goal, four to six cycles)[57, 60, 61, 58, 68] +/- ramucirumab 10 mg/kg IV[73] or
Pemetrexed 500 mg/m2 IV on day 1 (non-squamous histology) every 21 d (goal, four to six cycles; include folate and vitamin B12 supplements along with dexamethasone premedication for pemetrexed)[68] or
Erlotinib 150 mg PO daily for patients with EGFR mutation or gene amplification; given until disease progression[7, 34, 74, 75, 76, 77, 78, 79, 80]
Afatinib 40 mg PO daily for patients with metastatic squamous NSCLC that has progressed after platinum-based chemotherapy[81]
Sotorasib 960 mg PO daily for KRAS G12C–mutated locally advanced or metastatic NSCLC in adults who have received at 1 prior systemic therapy; continue until disease progression or unacceptable toxicity[82]
A study by Herbst et al confirms that bevacizumab and erlotinib should not be used together for refractory or recurrent NSCLC at this time; erlotinib alone in second-line and third-line settings remains the standard of care.[83]

Third-Line Therapy, Metastatic or Recurrent Disease

Stage IV or Recurrent Disease

Third-line therapy is given for advanced or recurrent non–small cell lung cancer (NSCLC) after disease progression following first-line and second-line therapy. Options include erlotinib, ramucirumab, and nivolumab.

Erlotinib is indicated for patients with EGFR mutation or gene amplification. It is given in a dosage of 150 mg PO daily until disease progression.[7, 34, 74, 75, 76, 77, 78, 79, 80]

Ramucirumab is indicated for metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab. The regimen is as follows:

Ramucirumab 10 mg/kg IV infused over ~1 h prior to docetaxel (75 mg/m2) IV infusion on day 1 of a 21-d cycle; continue until disease progression or unacceptable toxicity[73]

Nivolumab is indicated for metastatic squamous and nonsquamous (including adenomas) NSCLC with progression on or after platinum-based chemotherapy.[72]

The regimen is as follows:

Nivolumab: 240 mg IV q2wk or 480 mg q4wk over 30 min; continue until disease progression or unacceptable toxicity

Pembrolizumab is indicated for metastatic NSCLC in patients whose tumors express PD-L1 and who have disease progression on or after platinum-containing chemotherapy.[69] The regimen is as follows:

Pembrolizumab 200 mg IV q3wk or 400 mg IV q6wk; continue until disease progression or unacceptable toxicity (for up to 24 mo) ^[29]

Targeted Therapy, Metastatic or Recurrent Disease

Patients with metastatic (stage IV) or recurrent disease should undergo broad molecular testing to identify oncogenes or genetic alterations. Patients with actionable genetic alterations should be treated with corresponding targeted therapies; these are preferred over treatment with chemotherapy or immunotherapy.

EGFR mutations

Erlotinib, afatinib, osimertinib, and gefitinib are approved by the FDA for first-line treatment of metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test,[7] such as the cobas EGFR mutation test[84] and therascreen EGFR RGQ PCR Kit. Additionally, afatinib is indicated for first-line use in metastatic NSCLC for 3 additional nonresistant EGFR mutations (ie, L861Q, G719X, S768I).[85] Treatment recommendations include the following:

Osimertinib 80 mg PO once daily until disease progression or unacceptable toxicity
Erlotinib 150 mg PO daily until disease progression[7, 34, 74, 75, 76, 77, 78, 79, 80]
Afatinib 40 mg PO daily until disease progression[86]
Gefitinib 250 mg PO daily until disease progression[87, 88]
Dacomitinib 45 mg PO daily until disease progression[89, 90]

EGFR T790M mutation–positive NSCLC detected by an FDA-approved test, in patients whose disease has progressed on or after EGFR TKI therapy:

Osimertinib 80 mg PO once daily until disease progression or unacceptable toxicity ^[91]

EGFR exon 20 insertion–positive NSCLC detected by an FDA approved test, in who have progressed has progressed on or after platinum-based chemotherapy, treatment is with amivantamab or mobocertinib. Dosages are based on baseline body weight. [7, 92]

Amivantamab: Baseline body weight < 80 kg:

Week 1: Day 1, 350 mg IV x 1 dose; Day 2, 700 mg IV x 1 dose
Weeks 2-4: 1050 mg IV weekly
After Week 4: 1050 mg IV q2Weeks
Continue until disease progression or unacceptable toxicity

Amivantamab: Baseline body weight ≥80 kg:

Week 1: Day 1, 350 mg IV x 1 dose; Day 2: 1050 mg IV x 1 dose
Weeks 2-4: 1400 mg IV weekly
After Week 4: 1400 mg IV q2Weeks
Continue until disease progression or unacceptable toxicity

Mobocertinib: 160 mg PO once daily; continue until disease progression or unacceptable toxicity

Other mutations

ROS-1 mutation positive NSCLC:

Crizotinib 250 mg PO q12h until disease progression or unacceptable toxicity ^[93]
Entrectinib 600 mg PO once daily until disease progression or unacceptable toxicity ^{[94, 95]}

ALK-positive metastatic NSCLC:

Ceritinib 450mg PO once daily until disease progression or unacceptable toxicity ^[96]
Alectinib 600mg PO q12h until disease progression or unacceptable toxicity ^[97]
Lorlatinib 100 mg PO once daily until disease progression or unacceptable toxicity ^{[98, 99]}
crizotinib 250 mg po q12h unti disease progression or unacceptable toxicity ^[100]
Brigatinib 90 mg PO once daily for the first 7 days; if 90 mg/day is tolerated, increase the dose to 180 mg PO until disease progression or unacceptable toxicity ^[101]

BRAF V600E mutation-positive NSCLC:

Dabrafenib 150 mg PO BID plus trametinib 2 mg PO qDay ^[102]

MET exon 14 skipping mutation–positive NSCLC:

Capmatinib 400 mg PO BID; continue until disease progression or unacceptable toxicity ^[103]
Crizotinib 250 mg PO q12h until disease progression or unacceptable toxicity
Tepotinib 450 mg PO qDay until disease progression or unacceptable toxicity ^[104]

RET fusion–positive NSCLC:

Selpercatinib 120 mg PO BID (weight < 50 kg) or 160 mg PO BID (weight 50 kg or greater); continue until disease progression or unacceptable toxicity ^[105]
Pralsetinib 400 mg PO qDay on an empty stomach; continue until disease progression or until unacceptable toxicity ^[106]

NTRK mutation–positive NSCLC:

Larotrectinib 100 mg PO q12h until disease progression or unacceptable toxicity
Entrectinib 600 mg PO once daily until disease progression or unacceptable toxicity

KRAS G12C mutation–positive NSCLC:

Sotorasib 960 mg PO daily until disease progression or unacceptable toxicity ^[82]

Maintenance Chemotherapy, Metastatic or Recurrent Disease

Stage IV Disease

Maintenance chemotherapy may be considered for patients with advanced (stage IV) disease who have a disease response or stable disease after completing first-line chemotherapy

Switch Maintenance Chemotherapy

Switch maintenance chemotherapy involves giving chemotherapy with agents different from those used in first-line therapy. This chemotherapy is started after completion of first-line chemotherapy and continued until disease progression or unacceptable toxicities occur. Switch maintenance therapy is associated with improvements in progression-free survival for all three agents listed below and improvements in overall survival for pemetrexed and erlotinib.

Switch maintenance chemotherapy regimens are as follows:

Docetaxel 75 mg/m2 IV every 21 d or
Pemetrexed 500 mg/m2 IV every 21 d[107] (non-squamous histology) or
Erlotinib 150 mg PO daily (1 h before or 2 h after meals)[108]

Continuation Maintenance Therapy

Continuation maintenance therapy involves giving chemotherapy that was part of the first-line therapy, after completion of four to six cycles of first-line therapy. This chemotherapy is continued until disease progression or unacceptable toxicities occur. The following regimens have been associated with improvements in progression-free survival and overall survival:

Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 every 21 d; continue bevacizumab every 21 d after four to six cycles completed, until disease progression for patients who meet eligibility requirements (non-squamous histology, treated brain metastases, no history of hemoptysis)[45]
Carboplatin AUC 6 IV on day 1 plus pemetrexed 500 mg/m2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 every 21 d; after four cycles have been completed, pemetrexed and bevacizumab are continued until disease progression (include folate and vitamin B12 supplements along with dexamethasone premedication for pemetrexed)[46]
Cisplatin 75 mg/m2 IV on day 1 plus pemetrexed 500 mg/m2 IV on day 1 every 21 d; after four cycles have been completed, pemetrexed is continued until disease progression (include folate and vitamin B12 supplements along with dexamethasone premedication for pemetrexed)[109]

Special Considerations

Patients at any stage should be considered for participation in clinical trials in addition to standard of care.

Preoperative Staging and Imaging

Patients with certain situations who are being considered for curative surgical resection should undergo invasive mediastinal staging and extrathoracic imaging (head computed tomography (CT) or magnetic resonance imaging (MRI) with either whole-body positron-emission tomography (PET) or abdominal CT plus bone scan. Involvement of mediastinal nodes and/or metastatic disease represents a contraindication to resection. These situations are as follows[14, 7] :

Pancoast tumor (superior sulcus tumor)
Clinical T4N0/1M0 tumors
Two synchronous primary NSCLCs
A metachronous NSCLC
Stage I or II primary lung cancer with an isolated brain metastasis
Isolated adrenal metastasis
NSCLC tumor invading the chest wall

Histology

Histology must be determined by pathologic review for NSCLC. Histologic findings may influence therapeutic choices, as follows:

Pemetrexed is indicated for non-squamous tumors only.[14, 7]
Bevacizumab is contraindicated for squamous tumors due to the risk of pulmonary hemorrhage.
Erlotinib has higher response rates for adenocarcinomas with EGFR mutations.
Erlotinib should be considered for patients with EGFR mutations (activating mutations in exons 19 or 21); patients with the highest response rates typically are Asian, female, have never smoked or are light smokers, and have adenocarcinomas; response rates in unselected populations can be 10-20% or lower but increase to up to 90% in selected populations.[7, 34, 74, 75, 76, 77, 78, 79, 80]

Questions & Answers

Overview

What are the treatment recommendations for non-small cell lung cancer (NSCLC) stage IB or stage II?

What are the adjuvant chemotherapy regimens for non-small cell lung cancer (NSCLC) stage I or II?

What are the treatment recommendations for non-small cell lung cancer (NSCLC) stage III?

What are the concurrent chemotherapy/radiation therapy regimens for non-small cell lung cancer (NSCLC) stage III?

What are the sequential chemotherapy/radiation therapy regimens for non-small cell lung cancer (NSCLC) stage III?

What are the NCCN recommendations for consolidation therapy for non-small cell lung cancer (NSCLC) stage III?

What are the guidelines for the use of pembrolizumab in treatment of stage IIIa or IIIb non-small cell lung cancer (NSCLC)?

What are the first-line treatment recommendations for non-small cell lung cancer (NSCLC) stage IV or recurrent disease?

What are the first-line treatment options for metastatic (stage IV) non-small cell lung cancer (NSCLC) in patients who are not candidates for targeted therapies?

What are the single-agent therapy recommendations for non-small cell lung cancer (NSCLC) stage IV or recurrent disease?

What are the guidelines for PD-1/PD-L1 inhibitors for treatment of metastatic (stage IV) non-small cell lung cancer (NSCLC)?

What are the second-line treatment recommendations for non-small cell lung cancer (NSCLC) stage IV or recurrent disease?

What are the third-line treatment recommendations for non-small cell lung cancer (NSCLC) stage IV or recurrent disease?

What are the single-agent therapy recommendations for specific genetic mutations in non-small cell lung cancer (NSCLC) stage IV or recurrent disease?

What are the recommendations for maintenance chemotherapy for non-small cell lung cancer (NSCLC) stage IV or recurrent disease?

What are the recommendations for switch maintenance chemotherapy for non-small cell lung cancer (NSCLC) stage IV or recurrent disease?

What are the recommendations for continuation maintenance chemotherapy for non-small cell lung cancer (NSCLC) stage IV or recurrent disease?

Which patients with non-small cell lung cancer (NSCLC) should undergo intensive preoperative staging and imaging?

What is the role of histology in treatment selection for non-small cell lung cancer (NSCLC)?

Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008. 26:3552-9.
Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004. 350:351-60.
Arriagada R, Dunant A, Pignon JP, et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010. 28:35-42.
Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006. 7:719-27.
Pepe C, Hasan B, Winton TL, et al. Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol. 2007. 25:1553-61.
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. 352:2589-97.
[Guideline] NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. NCCN Guidelines. Available at http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Version 2.2022 — March 7, 2022; Accessed: March 8, 2022.
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. 21:3016-24.
Otto MA. FDA Approves Neoadjuvant Nivolumab/Chemo for Early-Stage NSCLC. Medscape Medical News. Available at https://www.medscape.com/viewarticle/969733. March 4, 2022; Accessed: March 8, 2022.
Strauss GM, Herndon J, Maddaus MA, et al. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection of stage IB non-small cell lung cancer (NSCLC): report of Cancer and Leukemia Group B (CALGB) protocol 9633. 2004 ASCO annual meeting, Abstract 7019.
Strauss GM, Herndon JE, Maddaus MA, et al. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): update of Cancer and Leukemia Group B (CALGB) protocol 9633. 2006 ASCO annual meeting, Abstract 7007.
Usami N, Yokoi K, Hasegawa Y, Taniguchi H, Shindo J, Yamamoto M, 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 Dec. 15 (6):583-7. [QxMD MEDLINE Link].
Zhang L, Ou W, Liu Q, Li N, Liu L, Wang S. Pemetrexed plus carboplatin as adjuvant chemotherapy in patients with curative resected non-squamous non-small cell lung cancer. Thorac Cancer. 2014 Jan. 5 (1):50-6. [QxMD MEDLINE Link].
Pazdur R, Wagman L, Camphausen K, Hoskins W, eds. Cancer Management: A Multidisciplinary Approach. 12th ed. Norwalk, Connecticut: CMP Healthcare Media LLC; 2009.
Herbst RS, O'Neill VJ, Fehrenbacher L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol. 2007. 2007:4743-50.
Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol. 2007. 25:313-8.
Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol. 2008. 26:5755-60.
Albain KS, Crowley JJ, Turrisi AT 3rd, 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. 20:3454-60.
Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol. 2003. 21:2004-10.
Hanna NH, Neubauer M, Ansari R, et al. Phase III trial of cisplatin (P) plus etoposide (E) plus concurrent chest radiation with or without consolidation docetaxel (D) in patients (pts) with inoperable stage III non-small cell lung cancer (NSCLC): HOG LUN 01-24/USO-023. 2007 ASCO annual meeting, Abstract 7512.
Curran WJ, Scott CB, Langer CJ, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III nsclc: RTOG 9410. 2003 ASCO annual meeting, Abstract 2499.
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. 23:5883-91.
Choy H, Akerley W, Safran H, et al. Multiinstitutional phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer. J Clin Oncol. 1998. 16:3316-22.
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 Aug 10. 29(23):3120-5. [QxMD MEDLINE Link]. [Full Text].
Vokes EE, Senan S, Treat JA, Iscoe NA. PROCLAIM: A phase III study of pemetrexed, cisplatin, and radiation therapy followed by consolidation pemetrexed versus etoposide, cisplatin, and radiation therapy followed by consolidation cytotoxic chemotherapy of choice in locally advanced stage III non-small-cell lung cancer of other than predominantly squamous cell histology. Clin Lung Cancer. 2009 May. 10(3):193-8. [QxMD MEDLINE Link].
Dillman RO, Herndon J, Seagren SL, Eaton WL, Jr., Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst. 1996. 88:1210-5.
Blum RH, Cooper J, Schmidt AM, et al. Cisplatin and vinblastine chemotherapy for metastatic non-small cell carcinoma followed by irradiation in patients with regional disease. Cancer Treat Rep. 1986. 70:333-7.
Antonia SJ, et al; PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16. 377 (20):1919-1929. [QxMD MEDLINE Link].
Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co. April 2020. Available at [Full Text].
Park JO, Kim SW, Ahn JS, et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007. 25:5233-9.
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. 346:92-8.
Gridelli C, Maione P, Illiano A, et al. Cisplatin plus gemcitabine or vinorelbine for elderly patients with advanced non small-cell lung cancer: the MILES-2P studies. J Clin Oncol. 2007. 25:4663-9.
Brodowicz T, Krzakowski M, Zwitter M, et al. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006. 52:155-63.
Lilenbaum R, Axelrod R, Thomas S, et al. Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2. J Clin Oncol. 2008. 26:863-9.
Belani CP, Ramalingam S, Perry MC, et al. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol. 2008. 26:468-73.
Ramalingam S, Barstis J, Perry MC, et al. Treatment of elderly non-small cell lung cancer patients with three different schedules of weekly paclitaxel in combination with carboplatin: subanalysis of a randomized trial. J Thorac Oncol. 2006. 1:240-4.
Ramalingam S, Perry MC, La Rocca RV, et al. Comparison of outcomes for elderly patients treated with weekly paclitaxel in combination with carboplatin versus the standard 3-weekly paclitaxel and carboplatin for advanced nonsmall cell lung cancer. Cancer. 2008. 113:542-6.
Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, 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 Jun 10. 30(17):2055-62. [QxMD MEDLINE Link].
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. 23:8380-8.
Helbekkmo N, Sundstrom SH, Aasebo U, et al. Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity. Br J Cancer. 2007. 97:283-9.
Gronberg BH, Bremnes RM, Flotten O, et al. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009. 27:3217-24.
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. 49:233-40.
Reck M, Schenker M, et al. Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. Eur J Cancer. 2019 Jul. 116:137-147. [QxMD MEDLINE Link]. [Full Text].
Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Nov 22. 379 (21):2040-2051. [QxMD MEDLINE Link].
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. 355:2542-50.
Patel JD, Bonomi P, Socinski MA, et al. Treatment rationale and study design for the pointbreak study: a randomized, open-label phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2009 Jul. 10(4):252-6. [QxMD MEDLINE Link].
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018 May 31. 378 (22):2078-2092. [QxMD MEDLINE Link]. [Full Text].
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Oct 8. [QxMD MEDLINE Link]. [Full Text].
Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, 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 Apr 4. [QxMD MEDLINE Link].
Georgoulias V, Papadakis E, Alexopoulos A, et al. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet. 2001. 357:1478-84.
Hainsworth JD, Spigel DR, Farley C, et al. Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network. Cancer. 2007. 110:2027-34.
Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003. 95:362-72.
Frasci G, Lorusso V, Panza N, et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000. 18:2529-36.
Gridelli C, Gallo C, Shepherd FA, et al. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003. 21:3025-34.
Tester WJ, Jin PY, Reardon DH, Cohn JB, Cohen MH. Phase II study of patients with metastatic nonsmall cell carcinoma of the lung treated with paclitaxel by 3-hour infusion. Cancer 1997;79:724-9.77. Millward MJ, Bishop JF, Friedlander M, et al. Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol. 1996. 14:142-8.
Millward MJ, Bishop JF, Friedlander M, et al. Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol. 1996. 14:142-8.
Chen YM, Shih JF, Perng RP, Tsai CM, Whang-Peng J. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest. 2006. 129:1031-8.
Schuette W, Nagel S, Blankenburg T, et al. Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel. J Clin Oncol. 2005. 23:8389-95.
Bria E, Cuppone F, Ciccarese M, et al. Weekly docetaxel as second line chemotherapy for advanced non-small-cell lung cancer: meta-analysis of randomized trials. Cancer Treat Rev. 2006. 32:583-7.
Fidias P, Dakhil S, Lyss A, et al. Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: updated report with survival. 2007 ASCO annual meeting, Abstract LBA7516.
Ramlau R, Gervais R, Krzakowski M, et al. Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer. J Clin Oncol. 2006. 24:2800-7.
Manegold C, Drings P, von Pawel J, et al. A randomized study of gemcitabine monotherapy versus etoposide/cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer. Semin Oncol. 1997. 24:S8-13-S8-7.
Anderson H, Lund B, Bach F, Thatcher N, Walling J, Hansen HH. Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol. 1994. 12:1821-6.
Furuse K, Fukuoka M, Kuba M, et al. Randomized study of vinorelbine (VRB) versus vindesine (VDS) in previously untreated stage IIIB or IV non-small-cell lung cancer (NSCLC). The Japan Vinorelbine Lung Cancer Cooperative Study Group. Ann Oncol. 1996. 7:815-20.
Furuse K, Kubota K, Kawahara M, et al. A phase II study of vinorelbine, a new derivative of vinca alkaloid, for previously untreated advanced non-small cell lung cancer. Japan Vinorelbine Lung Cancer Study Group. Lung Cancer. 1994. 11:385-91.
Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer.The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst. 1999. 91:66-72.
Depierre A, Lemarie E, Dabouis G, Garnier G, Jacoulet P, Dalphin JC. A phase II study of Navelbine (vinorelbine) in the treatment of non-small-cell lung cancer. Am J Clin Oncol. 1991. 14:115-9.
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. 22:1589-97.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21. 372 (21):2018-28. [QxMD MEDLINE Link].
Tecentriq (atezolizumab) [package insert]. South San Francisco, CA: Genentech, Inc. May 2020. Available at [Full Text].
FDA Approves Cemiplimab-rwlc for Patients With NSCLC and High PD-L1 Expression. American Society of Clinical Oncology (ASCO) Post. Available at https://ascopost.com/news/february-2021/fda-approves-cemiplimab-rwlc-for-patients-with-nsclc-and-high-pd-l1-expression/. February 26, 2021; Accessed: March 16, 2021.
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9. 373 (2):123-35. [QxMD MEDLINE Link]. [Full Text].
Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, 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 Aug 23. 384(9944):665-73. [QxMD MEDLINE Link].
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005. 353:123-32.
Wheatley-Price P, Ding K, Seymour L, Clark GM, Shepherd FA. Erlotinib for advanced non-small-cell lung cancer in the elderly: an analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008. 26:2350-7.
Jänne PA, Wang X, Socinski MA, Crawford J, Stinchcombe TE, Gu L, et al. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. J Clin Oncol. 2012 Jun 10. 30 (17):2063-9. [QxMD MEDLINE Link]. [Full Text].
Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, et al. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2012 Nov. 13 (11):1161-70. [QxMD MEDLINE Link]. [Full Text].
Paz-Ares L, Sanchez JM, García-Velasco A, et al. A prospective phase II trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR). 2006 ASCO annual meeting, Abstract 7020.
Zhou C, Wu Y-L, Chen G, et al. Efficacy results from the randomised phase 3 OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM) in Chinese advanced non-small-cell lung cancer (NSCLC) patients (pts) with EGFR activating mutations. 2010 European Society of Medical Oncology Congress, Abstract LBA13.
Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 Sep 1. 23 (25):5892-9. [QxMD MEDLINE Link].
Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015 Aug. 16 (8):897-907. [QxMD MEDLINE Link].
Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N Engl J Med. 2021 Jun 24. 384 (25):2371-2381. [QxMD MEDLINE Link].
Bral S, Gevaert T, Linthout N, et al. Prospective, risk-adapted strategy of stereotactic body radiotherapy for early-stage non-small-cell lung cancer: results of a Phase II trial. Int J Radiat Oncol Biol Phys. 2011 Aug 1. 80(5):1343-9. [QxMD MEDLINE Link].
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, 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 multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar. 13(3):239-46. [QxMD MEDLINE Link].
Gilotrif (afatinib) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. January, 2018. Available at [Full Text].
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Jul 1. [QxMD MEDLINE Link].
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014 Jan 7. 110 (1):55-62. [QxMD MEDLINE Link]. [Full Text].
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24. 362 (25):2380-8. [QxMD MEDLINE Link]. [Full Text].
Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, 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 Nov. 18 (11):1454-1466. [QxMD MEDLINE Link].
Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al. Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. J Clin Oncol. 2018 Aug 1. 36 (22):2244-2250. [QxMD MEDLINE Link].
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30. 372 (18):1689-99. [QxMD MEDLINE Link]. [Full Text].
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 (abstract 0914). J Clin Oncol. 2021. 39(suppl 15):[Full Text].
Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Nov 20. 371 (21):1963-71. [QxMD MEDLINE Link]. [Full Text].
Ahn MJ, BCC, Siena S, Drilon A, et al. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC) Abstract OA14.06. Presented at the IASLC 18th World Conference on Lung Cancer; Yokohama, Japan. 2017. J Thoracic Onc. 2017 Nov;12(11; suppl 2):S1783.
Drilon A, Barlesi F, DeBraud F, Cho BC, Ahn MJ, Seina S, et al. Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2 (abstract CT192). Presented at the American Association for Cancer Research (AACR) Annual Meeting 2019 March 29-April 3. Atlanta, GA. [Full Text].
Zykadia (ceritinib) [package insert]. East Hanover, New Jersey 07936: Novartis Pharmaceuticals Corporation. 7/2017. Available at [Full Text].
Alectinib (Alecensa) [package insert]. 1 DNA Way South San Francisco, CA 94080-4990: Genentech USA, Inc. 11/2017. Available at [Full Text].
Solomon BJ, Besse B, Bauer TM, Felip E, Soo RA, Camidge DR, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018 Nov 6. [QxMD MEDLINE Link].
FDA approves lorlatinib for metastatic ALK-positive NSCLC. FDA. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-lorlatinib-metastatic-alk-positive-nsclc. March 3, 2021; Accessed: March 4, 2021.
Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4. 371 (23):2167-77. [QxMD MEDLINE Link].
Kim DW, Tiseo M, Ahn MJ, Reckamp KL, Hansen KH, Kim SW, 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 May 5. JCO2016715904. [QxMD MEDLINE Link].
Planchard D, Besse B, Groen HJM, Souquet PJ, 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 Jul. 17 (7):984-993. [QxMD MEDLINE Link]. [Full Text].
Tabrecta (capmatinib) [package insert]. East Hanover NJ: Novartis Pharmaceuticals Corporation. 2020 May. Available at [Full Text].
FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. FDA. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-tepotinib-metastatic-non-small-cell-lung-cancer. February 3, 2021; Accessed: February 24, 2021.
Retevmo (selpercatinib) [package insert]. Indianapolis, IN: Eli Lilly. 2020 May. Available at [Full Text].
Gavreto (pralsetinib) [package insert]. Cambridge, MA: Blueprint Medicines Corporation. September 2020. Available at [Full Text].
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. 374:1432-40.
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. 11:521-9.
Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar. 13(3):247-55. [QxMD MEDLINE Link].
Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009. 373:1525-31.
Pirker R, Szczesna A, Pawel Jv, et al. FLEX: a randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). 2008 ASCO annual meeting, Abstract 3.
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 Dec. 20 (12):1655-1669. [QxMD MEDLINE Link].

Non-Small Cell Lung Cancer (NSCLC) Treatment Protocols

Treatment Recommendations, Early or Localized Disease

Stage IB (> 4 cm tumor size) or II disease

Neoadjuvant and adjuvant chemotherapy regimens for stage IB or II NSCLC

Treatment of Locally Advanced Disease

Stage IIIa or IIIb disease

Concurrent chemotherapy/radiation therapy regimens

Sequential chemotherapy/radiation therapy regimens

Consolidation therapy

Immunotherapy for patients who are not candidates for surgery or definitive chemoradiation

First-Line Therapy, Metastatic (Stage IV) or Recurrent Disease

Stage IV or Recurrent Disease

Single-Agent Therapy

PD-1/PD-L1 Inhibitors

Second-Line Therapy, Metastatic or Recurrent Disease

Stage IV or Recurrent Disease

Third-Line Therapy, Metastatic or Recurrent Disease

Stage IV or Recurrent Disease

Targeted Therapy, Metastatic or Recurrent Disease

EGFR mutations

Other mutations

Maintenance Chemotherapy, Metastatic or Recurrent Disease

Stage IV Disease

Switch Maintenance Chemotherapy

Continuation Maintenance Therapy

Special Considerations

Preoperative Staging and Imaging

Histology

Questions & Answers

Contributor Information and Disclosures

References