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?

Answer

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^{[29, 30]} or
Cisplatin 100 mg/m² IV on day 1 plus gemcitabine 1000 mg/m² IV on days 1, 8, and 15 every 28 d^[30] or
Cisplatin 60 mg/m² IV on day 1 plus gemcitabine 1000 mg/m² IV on days 1 and 8 every 21 d^{[31, 32]} or
Cisplatin 75 mg/m² IV on day 1 plus docetaxel 75 mg/m² IV on day 1 every 21 d^{[8, 30]} or
Carboplatin AUC 6 IV on day 1 plus paclitaxel 175-225 mg/m² IV on day 1 every 21 d^{[30, 33]} or
Carboplatin AUC 6 IV on day 1 plus paclitaxel 90 mg/m² IV on days 1, 8, and 15 every 28 d^{[34, 35, 36]} 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^[37] or
Carboplatin AUC 6 IV on day 1 plus docetaxel 75 mg/m² IV on day 1 every 21 d^[19] or
Carboplatin AUC 5 IV on day 1 plus gemcitabine 1250 mg/m² IV on days 1 and 8 every 21 d^{[38, 39, 40]} 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^[31] or
Carboplatin AUC 5 IV on day 1 plus vinorelbine 30 mg/m² IV on days 1 and 8 every 21 d^[41]

Combination immunotherapy for first-line treatment of metastatic NSCLC with PD-L1 tumor expression ≥1% is as follows^[42]:

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 ^[37] 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 ^[43]; alternative pembrolizumab dose is 400 mg q6wk ^[28]

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)^[44] 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^[14]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)^[45]

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:^[46]

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:^{[47, 48]}

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:^[46]

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^{[49, 50]} 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^{[41, 51, 52, 53]}

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