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 This is an original JCO publication from 2015. Please visit the JCO website to access the full articles.


Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer Guideline


 

 Authors

Gregory A. Masters, Sarah Temin, Christopher G. Azzoli, Giuseppe Giaccone, Sherman Baker Jr, Julie R. Brahmer, Peter M. Ellis, Ajeet Gajra, Nancy Rackear, Joan H. Schiller, Thomas J. Smith, John R. Strawn, David Trent, and David H. Johnson

THE BOTTOM LINE

Special Announcement (October 19, 2015): The US FDA approved nivolumab for patients with NSCLC non-squamous histologies with progression on or after platinum-based chemotherapy on October 9, 2015, expanding upon the FDA’s previous approval for patients with metastatic squamous NSCLC with progression on or after platinum-based chemotherapy on March 4, 2015. The FDA also approved pembrolizumab for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 with disease progression on or after platinum-containing chemotherapy on October 2, 2015. ASCO guidelines are updated on a regular basis and the data accompanying these approvals will be examined during the next guideline update.

Recommendations for Systemic Treatment of Patients With Stage IV Non–Small-Cell Lung Cancer: ASCO Clinical Practice Guideline Update

Guideline Question

What systemic therapy treatment options should be offered to patients with stage IV non–small-cell lung cancer (NSCLC), depending on the subtype of the patient’s cancer?

Target Population

Patients with stage IV NSCLC.

Target Audience

This clinical practice guideline update is targeted at health care providers (including medical oncologists, nurses, social workers, and any other relevant members of comprehensive multidisciplinary cancer care teams), and patients and their caregivers in North America and beyond.

Methods

An Update Committee was convened to develop clinical practice guideline recommendations based on a systematic review of the medical literature.

Key Points

See Summary of Recommendations Table below for full details.

● There is no cure for patients with stage IV NSCLC.

● Decisions on chemotherapy should not be made on the basis of age alone

First-Line Treatment for Patients:

● Without an EGFR-sensitizing mutation or ALK gene rearrangement and performance status (PS) 0 to 1 (or appropriate PS 2): a variety of combination cytotoxic chemotherapies are recommended. Platinum-based doublets are preferred, along with early concurrent palliative care and symptom management. Based on tumor histology (ie, squamous v nonsquamous), there are some variations (evidence quality: high; strength of recommendation: strong).

● Adding bevacizumab to carboplatin plus paclitaxel is recommended if there are no contraindications (evidence quality: intermediate; strength of recommendation: moderate).

● With PS 2: combination or single-agent chemotherapy or palliative care alone may be used (chemotherapy: evidence quality: intermediate; strength of recommendation: weak; palliative care: evidence quality: intermediate; strength of recommendation: strong).

● With sensitizing EGFR mutations: afatinib, erlotinib, or gefitinib is recommended (evidence quality: high; strength of recommendation: strong for each).

● With ALK gene rearrangements: crizotinib is recommended (evidence quality: intermediate; strength of recommendation: moderate).

● With ROS1 rearrangement: crizotinib is recommended (type: informal consensus; evidence quality: low; strength of recommendation: weak).

● With large-cell neuroendocrine carcinoma: platinum plus etoposide or the same treatment as other patients with nonsquamous carcinoma may be administered (type: informal consensus; evidence quality: low; strength of recommendation: weak).

● First-line cytotoxic chemotherapy should be stopped at disease progression or after four cycles in patients with nonresponsive stable disease (no change).

● With stable disease or response after four cycles of a first-line pemetrexed-containing regimen: pemetrexed continuation maintenance may be used; if initial regimen does not contain pemetrexed, an alternative chemotherapy (switch) may be used, or a break from chemotherapy may be recommended until disease progression (addition of pemetrexed: evidence quality: intermediate; strength of recommendation: moderate).

Second-Line Treatment for Patients:

● With nonsquamous cell carcinoma (NSCC): docetaxel, erlotinib, gefitinib, or pemetrexed are acceptable (evidence quality: high; strength of recommendation: strong).

● With SCC: docetaxel, erlotinib, or gefitinib are acceptable (evidence quality: high; strength of recommendation: strong).

● With sensitizing EGFR mutations who did not respond to a first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI): combination cytotoxic chemotherapy is recommended for those with NSCC, as listed in under first-line treatment (type: informal consensus; evidence quality: intermediate; strength of recommendation: strong).

● With sensitizing EGFR mutations who received a first-line EGFR TKI and experienced disease progression after an initial response: may be switched to chemotherapy or another EGFR TKI as second-line therapy (type: informal consensus; evidence quality: low; strength of recommendation: weak).

● With ALK rearrangement and progression after first-line crizotinib: chemotherapy or ceritinib may be offered (chemotherapy: evidence quality: high; strength of recommendation: strong; ceritinib: evidence quality: intermediate; strength of recommendation: moderate).

Third-Line Treatment for Patients:

● Who have not received erlotinib or gefitinib and have PS 0 to 3: erlotinib may be recommended.

● Data are insufficient to recommend routine third-line cytotoxic drugs.

Note.

For all recommendations, benefits outweigh harms. The type of recommendation is evidence based, except where otherwise noted. ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate.

Additional Resources

More information, including a Data Supplement with additional evidence tables, a Methodology Supplement with information about evidence quality and strength of recommendations, slide sets, and clinical tools and resources, is available at http://www.asco.org/guidelines/nsclc. Patient information is available at http://www.cancer.net.

SUMMARY OF RECOMMENDATIONS

Clinical QuestionRecommendationEvidence Rating
Which patients with stage IV NSCLC should be treated with chemotherapy?For patients with performance status (PS) of 0 or 1, a combination of two cytotoxic drugs is recommended. Platinum combinations are recommended over nonplatinum therapy; however, nonplatinum therapy combinations are recommended for patients who have contraindications to platinum therapy. Chemotherapy also may be used to treat selected patients with PS 2 who desire aggressive treatment after a thorough discussion of the risks and benefits of such treatment.

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

Because there is no cure for patients with stage IV NSCLC, early concomitant assistance of palliative care has improved the survival and well-being of patients and is therefore recommended.

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

First-line Therapy
What is the most effective first-line therapy for patients with stage IV NSCLC with nonsquamous cell carcinoma, negative or unknown EGFR-sensitizing mutation and ALK gene rearrangement status, and PS 0-1 or possibly PS 2?

Cisplatin-based Combinations

  • cisplatin/docetaxel
  • cisplatin/paclitaxel
  • cisplatin/pemetrexed
  • cisplatin/vinorelbine

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

Carboplatin-based Combinations

  • carboplatin/nab albumin-bound paclitaxel
  • carboplatin/paclitaxel
  • carboplatin/pemetrexed
  • carboplatin/docetaxel

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

Nonplatinum Doublets

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Weak

What is the most effective first-line therapy for patients with stage IV NSCLC with negative or unknown EGFR/ALK status, NSCC, and no contraindications to bevacizumab?For patients receiving carboplatin/paclitaxel, the Update Committee recommends the addition of bevacizumab, 15 mg/kg every 3 weeks, except for patients with SCC histologic type, brain metastases, clinically significant hemoptysis, inadequate organ function, Eastern Cooperative Oncology Group PS greater than1, therapeutic anticoagulation, clinically significant cardiovascular disease, or medically uncontrolled hypertension. Bevacizumab may be continued, as tolerated, until disease progression.

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Moderate

There is insufficient evidence to recommend (for or against) pemetrexed in combination with bevacizumab/carboplatin for patients who do not have contraindications to bevacizumab. 
What is the most effective first-line therapy for patients with stage IV NSCLC with PS 2, NSCC, and negative or unknown EGFR-sensitizing mutation and ALK gene rearrangement status?In the context of shared decision-making, combination therapy, single-agent chemotherapy, or palliative therapy alone may be used for patients in this population with PS 2.

Chemotherapy:

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Weak

Palliative Care:

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Strong

What is the most effective first-line therapy for patients with stage IV NSCLC with SCC, negative or unknown EGFR-sensitizing mutation and ALK gene rearrangement status, and PS 0-1 or possibly PS 2?Patients with the characteristics listed in Clinical Question A3 and with SCC histology should be offered the following options:

Cisplatin-based Combinations

  • cisplatin/docetaxel
  • cisplatin/gemcitabine
  • cisplatin/paclitaxel
  • cisplatin/vinorelbine

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

Carboplatin-based Combinations

  • carboplatin/gemcitabine
  • carboplatin/paclitaxel
  • carboplatin/nab albumin-bound paclitaxel
  • carboplatin/docetaxel

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

Nonplatinum Doublets

Type: Evidence-Based, Benefits Outweigh Harms

Evidence Quality: Low

Strength of Recommendation: Weak

What is the most effective first therapy for patients with stage IV NSCLC with negative or unknown EGFR/ALK status, SCC, and PS 2?In the context of shared decision making:
Combination chemotherapy or single-agent chemotherapy

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Weak

Palliative therapy alone

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Strong

What is the most effective first-line therapy for patients with stage IV NSCLC with an EGFR-sensitizing mutation and PS 0-1 or possibly PS 2?If patients have stage IV NSCLC and a sensitizing EGFR mutation, first-line (options are):
afatinib

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

erlotinibType: Evidence-Based; Benefits Outweigh Harms Evidence Quality: High Strength of Recommendation: Strong
gefitinib

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

What is the most effective first-line therapy for patients with stage IV NSCLC with ALK gene rearrangement and PS 0-1 or possibly PS 2?If patients have stage IV NSCLC and ALK rearrangements, first-line crizotinib is recommended.

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Moderate

What is the most effective first-line therapy for patients with stage IV NSCLC with ROS1 rearrangement, no ALK gene rearrangement, negative/unknown EGFR-sensitizing mutation status, and PS 0-1 or possibly PS 2?If patients have stage IV NSCLC with ROS1 rearrangement, single-agent crizotinib is recommended, because it has shown some results indicating improved response rate and duration of response.

Type: Informal Consensus; Benefits Outweigh Harms

Evidence Quality: Low

Strength of Recommendation: Weak

What is the most effective first-line therapy for patients with stage IV NSCLC with negative or unknown EGFR/ALK status and large cell neuroendocrine carcinoma?Patients with large cell neuroendocrine carcinoma may receive the same treatment as other patients with NSCC or treatment with etoposide in platinum combinations.

Type: Informal Consensus; Benefits Outweigh Harms

Evidence Quality: Low

Strength of Recommendation: Weak

What is the best chemotherapy for treatment of the elderly with stage IV NSCLC?Decisions on the selection of chemotherapy should not be made or altered based on age alone.

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

Duration
What is the optimal treatment for patients with stable disease or response after four cycles of cytotoxic chemotherapy?In patients with stage IV NSCLC, first-line cytotoxic chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is stable but not responding to treatment; two-drug cytotoxic combinations should be administered for no more than six cycles.No change from prior version.

For patients with stable disease or response after four cycles of a first-line pemetrexed-containing regimen, continuation maintenance treatment with pemetrexed is recommended.

For patients with stable disease or response after four cycles of a regimen that did not include a pemetrexed-containing combination, alternative, single-agent chemotherapy such as pemetrexed in patients with nonsquamous histology, docetaxel in unselected patients, or erlotinib in unselected patients, or a break from cytotoxic chemotherapy with initiation of second-line chemotherapy at disease progression may be recommended.

For the addition of pemetrexed:

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Moderate

Second-line therapy
What is the most effective second-line therapy for patients with stage IV NSCLC with negative or unknown EGFR/ALK status and NSCC?For patients with advanced NSCLC, NSCC, negative or unknown EGFR/ALK status, and adequate PS when the disease has progressed during or after first-line platinum-based therapy, docetaxel, erlotinib, gefitinib, or pemetrexed are acceptable as second-line therapy.

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

What is the most effective second-line therapy for patients with stage IV NSCLC with negative or unknown EGFR/ALK status and SCC?For patients with advanced NSCLC, SCC, negative or unknown EGFR/ALK status, and adequate PS when the disease has progressed during or after first-line, platinum-based therapy, docetaxel, erlotinib, or gefitinib are acceptable as second-line therapy.

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

What is the most effective second-line therapy for patients with stage IV NSCLC with a sensitizing EGFR mutation who received a first-line EGFR TKI and experienced disease progression?For patients with a sensitizing EGFR mutation(s) who did not respond to a firstline EGFR TKI, cytotoxic chemotherapy is recommended, following the first-line recommendations for patients with NSCC.

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Strong

What is the most effective second-line therapy for patients with stage IV NSCLC with a sensitizing EGFR mutation who received a first-line EGFR TKI and experienced disease progression after an initial response?Patients who received an EGFR TKI in the first-line setting, had an initial response, and subsequently experienced disease progression, may be switched to chemotherapy or another EGFR TKI as second-line therapy.

Type: Informal Consensus; Balance of Benefits and Harms

Evidence Quality: Low

Strength of Recommendation: Weak

What is the most effective second-line therapy for patients with stage IV NSCLC with ALK rearrangement with progression after first-line crizotinib?Patients whose tumor(s) have ALK rearrangements and who received crizotinib in the first-line may be offered the option of:
chemotherapy (after first-line recommendations for patients with NSCC)

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

ceritinib

Type: Evidence-Based; Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Moderate

What is the optimal second-line treatment for elderly patients with stage IV NSCLC?The evidence does not support the selection of a specific second-line chemotherapy drug or combination based on age alone.This recommendation has not changed. Age alone is not a contraindication to chemotherapy for NSCLC.
Third-line Therapy
Is there a role for third-line therapy or beyond in the treatment of stage IV NSCLC?When disease progresses on or after second-line chemotherapy, treatment with erlotinib may be recommended as third-line therapy for patients with a PS of 0 to 3 who have not received prior erlotinib or gefitinib.No change from prior version.
Data are not sufficient to make a recommendation for or against using cytotoxic drugs as third-line therapy; patients should consider experimental treatment, clinical trials, and continued best supportive (palliative) care.No change from prior version.

 

 

ASCO Guideline Disclaimer: The clinical practice guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (“ASCO”) to assist practitioners in clinical decision making. The information therein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating physician, as the information does not account for individual variation among patients. Recommendations reflect high, moderate or low confidence that the recommendation reflects the net effect of a given course of action.  The use of words like “must,” “must not,” “should,” and “should not” indicate that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating physician in the context of treating the individual patient. Use of the information is voluntary.  ASCO provides this information on an “as is” basis, and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.


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