Non-Small Cell Lung Cancer (NSCLC) Treatment Protocols

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-year survival of approximately 5% [1] ; median 5-year 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/m 2 IV on days 1 and 8 plus vinorelbine 25 mg/m 2 IV on days 1, 8, 15, and 22 every 28 d [1, 2, 3, 4, 5, 6] or

Cisplatin 100 mg/m 2 IV on day 1 plus vinorelbine 30 mg/m 2 on days 1, 8, 15, and 22 every 28 d [1, 2, 3, 4, 5, 6] or

Cisplatin 75-80 mg/m 2 IV on day 1 plus vinorelbine 25-30 mg/m 2 IV on days 1 and 8 every 21 d [1, 2, 3, 4, 5, 6] or

Cisplatin 80 mg/m 2 IV on days 1, 22, 43, and 64 plus vinblastine 4 mg/m 2 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/m 2 IV on day 1 plus gemcitabine 1250 mg/m 2 on days 1 and 8 every 21 d (preferred for squamous histologies) [7] or

Cisplatin 75 mg/m 2 IV on day 1 plus docetaxel 75 mg/m 2 IV on day 1 every 21 d (preferred for squamous histologies) [8] or

Cisplatin 75 mg/m 2 IV on day 1 plus pemetrexed 500 mg/m 2 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] :

Platinum-doublet chemotherapy consists of the following:

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 plus paclitaxel 200 mg/m 2 IV on day 1 every 21 d [10] (see the Carboplatin AUC Dose Calculation [Calvert formula] calculator)

Carboplatin AUC 5 IV on day 1 and pemetrexed 500 mg/m 2 IV on day 1 every 21 d (for non-squamous histologies) [12]

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 programmed death ligand 1 (PD-L1) ≥1% NSCLC in patients who previously received adjuvant chemotherapy. [7]

Treatment of Locally Advanced Disease

Stage IIIa or IIIb disease

Stages IIIa and IIIb NSCLC 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, 13, 14, 15]

Concurrent chemotherapy/radiation therapy regimens

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

Cisplatin 50 mg/m 2 IV on days 1, 8, 29, and 36 plus etoposide 50 mg/m 2 IV on days 1-5 and days 29-33 [16, 17, 18, 19] or

Carboplatin AUC 2 IV weekly for 7 wk plus paclitaxel 45 - 50 mg/m 2 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/m 2 IV on day 1 every 21 wk [20, 21] or

Carboplatin AUC 5 IV on day 1 plus pemetrexed 500 mg/m 2 IV on day 1 every 21 d for four cycles (for non-squamous histologies) [22] or

Cisplatin 75 mg/m 2 IV on day 1 plus pemetrexed 500 mg/m 2 IV on day 1 every 21 d for three cycles (for non-squamous histologies) [23]

Sequential chemotherapy/radiation therapy regimens

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

Cisplatin 100 mg/m 2 IV on days 1 and 29 plus vinblastine 5 mg/m 2 /weekly IV on days 1, 8, 15, 22, and 29, followed by radiation therapy [7, 15, 24, 25] or

Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m 2 IV on day 1 every 21 d for two cycles, followed by radiation therapy [7, 20, 21]

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 [26] :

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%. [27]

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. [13, 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:

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 100 mg/m 2 IV on day 1 plus gemcitabine 1000 mg/m 2 IV on days 1, 8, and 15 every 28 d [29] or

Cisplatin 60 mg/m 2 IV on day 1 plus gemcitabine 1000 mg/m 2 IV on days 1 and 8 every 21 d [30, 31] or

Carboplatin AUC 6 IV on day 1 plus paclitaxel 90 mg/m 2 IV on days 1, 8, and 15 every 28 d [33, 34, 35] or

Paclitaxel protein bound 100 mg/m 2 IV on days 1, 8, and 15 of every 21 d plus carboplatin AUC 6 IV on day 1 [36] or

Carboplatin AUC 5 IV on day 1 plus gemcitabine 1250 mg/m 2 IV on days 1 and 8 every 21 d [37, 38, 39] or

Combination immunotherapy for first-line treatment of metastatic NSCLC with PD-L1 tumor expression ≥1% is as follows [41] :

Nivolumab plus ipilimumab:

Continue until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression

Tremelimumab plus durvalumab (and platinum-based chemotherapy)

Tremelimumab 75 mg IV plus durvalumab 1500 mg IV [7, 42] :

Cycle 7 (week 20) and thereafter: Durvalumab and chemotherapy; continue durvalumab until disease progression or intolerable toxicity

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 [36] 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 [27] ​

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/m 2 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/m 2 IV on day 1 plus gemcitabine 1250 mg/m 2 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/m 2 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/m 2 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/m 2 plus cisplatin 75 mg/m 2 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/m 2 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)

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/m 2 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/m 2 IV on days 1 and 8 plus docetaxel 100 mg/m 2 IV on day 8 every 21 d [49, 50] or

Gemcitabine 1000-1200 mg/m 2 IV on days 1 and 8 plus vinorelbine 25-30 mg/m 2 IV on days 1 and 8 every 21 d [40, 51, 52, 53]

Single-Agent Therapy

Single-agent therapy is a reasonable first-line option in patients with good performance status (ECOG score ≤2) 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 whose tumors are EGFR-mutation positive. [7]

Single-agent regimens include the following:

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 with 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; dosage is as follows: [47, 68, 48]

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 [69]

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:

Second-Line Therapy, Metastatic 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 [71] 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 [68] ; alternative pembrolizumab dose is 400 mg IV q6wk or

Docetaxel 75 mg/m 2 IV on day 1 every 21 d (goal, four to six cycles) [56, 59, 60, 57, 67] +/- ramucirumab 10 mg/kg IV [72] or

Pemetrexed 500 mg/m 2 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) [67] or

Erlotinib 150 mg PO daily for patients with EGFR mutation or gene amplification; given until disease progression [7, 32, 73, 74, 75, 76, 77, 78, 79]

Afatinib 40 mg PO daily for patients with metastatic squamous NSCLC that has progressed after platinum-based chemotherapy [80]

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 [81]

Adagrasib 600 mg PO BID 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

Third-line therapy is given for advanced or recurrent 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, 32, 73, 74, 75, 76, 77, 78, 79]

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 those aberrations prior to receiving ramucirumab. The regimen is as follows:

Ramucirumab 10 mg/kg IV infused over ~1 h prior to docetaxel (75 mg/m 2 ) IV infusion on day 1 of a 21-d cycle; continue until disease progression or unacceptable toxicity [72]

Nivolumab is indicated for metastatic squamous and nonsquamous (including adenomas) NSCLC with progression on or after platinum-based chemotherapy. [71] 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. [68] 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) [27]

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: L861Q, G719X, and S768I. [85] Treatment recommendations include the following:

Osimertinib 80 mg PO daily plus pemetrexed 500 mg/m 2 IV and cisplatin 75 mg/m 2 (or carboplatin AUC 5) IV on Day 1 of 21-day cycles for four cycles, then osimertinib 80 mg PO daily for Cycle 5 and thereafter [86]

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

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

Amivantamab: Baseline body weight < 80 kg:

Amivantamab: Baseline body weight ≥80 kg:

Other mutations

ROS1 mutation–positive NSCLC:

Repotrectinib 160 mg PO qDay for 14 days, then increase to 160 mg PO BID; continue until disease progression or unacceptable toxicity [96]

ALK-positive metastatic NSCLC:

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 [102]

BRAF V600E mutation-positive NSCLC:

MET exon 14 skipping mutation–positive NSCLC:

RET fusion–positive NSCLC:

Pralsetinib 400 mg PO qDay on an empty stomach; continue until disease progression or until unacceptable toxicity [107]

NTRK mutation–positive NSCLC:

KRAS G12C mutation–positive NSCLC:

HER2 mutation–positive NSCLC:

Maintenance Chemotherapy, Metastatic or Recurrent 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. Two approaches to maintenance chemotherapy are used: switch and continuation.

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:

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/m 2 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) [44]

Carboplatin AUC 6 IV on day 1 plus pemetrexed 500 mg/m 2 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) [45]

Cisplatin 75 mg/m 2 IV on day 1 plus pemetrexed 500 mg/m 2 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) [111]

Special Considerations

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

Preoperative Staging and Imaging

In certain circumstances, patients 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 [13, 7] :

Histology

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

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, 32, 73, 74, 75, 76, 77, 78, 79]

Questions & Answers

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