ASCO Updates Stage IV NSCLC Treatment Guideline

Gregory Masters, MD

ASCO has updated its clinical practice guideline for the treatment of patients with stage IV non-small cell lung cancer (NSCLC), based on a systemic review of 73 randomized controlled trials that were published from January 2007 to February 2014.

ASCO's previous guideline on the treatment of patients with stage IV NSCLC was published in 2009, with an update on switch maintenance therapy added in 2011. The latest rendition of the guideline focuses on patient histology and molecular subtype for treatment selection.

"Although there is no cure for patients with stage IV non-small cell lung cancer, various treatment options are available that can help patients control their cancer longer," Gregory Masters, MD, co-chair of the ASCO Expert Panel that developed the guideline, said in a statement. "This guideline will help doctors choose the most appropriate therapies, depending on the biology of the tumor and the patient's general well-being."

The revised guideline contained information on a number of therapies, including afatinib, ceritinib, crizotinib, erlotinib, gefitinib, and maintenance therapy. However, given a lack of significant phase III clinical trial data at the time of the analysis, the guideline was unable to make a recommendation regarding the use of PD-1 inhibitors, like nivolumab or pembrolizumab.

"Since the systematic review was performed for this guideline, nivolumab has emerged for patients with squamous cell carcinoma in the second- and third-line settings who experience progression during or after platinum-based therapy," the authors of the guideline wrote. "The Update Committee will consider a future guideline revision regarding the published phase III data."

In conjunction with each systemic treatment recommendation, the guideline called for the utilization of palliative care. Early concomitant palliative care has been shown to improve survival for patients with advanced NSCLC, in addition to a number of other improvements, according to the authors of the recommendations that was published in the Journal of Clinical Oncology.

"Early palliative care is associated with improved survival of patients with advanced lung cancer," David H. Johnson, MD, co-chair of the ASCO Expert Panel, said in a statement. "Hospice care also improves patient quality of life and reduces caregiver distress."

For patients in the frontline setting, the updated guideline calls for the administration of a platinum-based chemotherapy doublet for patients with a performance status (PS) of 0 or 1 without an alteration in EGFR or ALK. For those with a PS of 2, chemotherapy or palliative care alone should be administered.

In the absence of contraindications, bevacizumab can be administered along with carboplatin and paclitaxel for patients with a PS of 0 to 1. In this setting, bevacizumab should be administered at 15 mg/kg every 3 weeks.

The addition of bevacizumab should be avoided in patients with squamous cell histology, clinically significant hemoptysis, inadequate organ function, and PS >1. The guideline noted a lack of evidence for the combination of pemetrexed with bevacizumab and carboplatin.

In the first-line setting for patients with sensitizing EGFR mutations, treatment with afatinib, erlotinib, or gefitinib should be utilized, the guideline suggested. Prior recommendations for the utilization of cetuximab were removed from the guideline. In tumors with ALK or ROS1 gene rearrangements, the initial treatment should consist of crizotinib. For patients with large-cell neuroendocrine carcinoma, the guideline recommended first-line platinum-based therapy plus etoposide.

Following an initial response to frontline therapy, various maintenance therapy strategies could be utilized, which include pemetrexed continuation, alternative chemotherapy, or a chemotherapy break. The guideline noted that at this time, switch maintenance strategies with pemetrexed and erlotinib have demonstrated improved overall survival (OS) and FDA approval. Additionally, continuation maintenance therapy with pemetrexed was recently found to extend OS.

Second-line treatments for patients with non-squamous histology should consist of docetaxel, erlotinib, gefitinib, or pemetrexed. Those with squamous cell carcinoma should receive docetaxel, erlotinib, or gefitinib. For patients with EGFR mutations, second-line chemotherapy or another EGFR inhibitor can be utilized, based on response to first-line EGFR inhibition.

At this time, the guideline committee could not make a recommendation concerning the utilization of third-generation EGFR inhibitors, like rociletinib (CO1686) or osimertinib (AZD9291). These agents target the acquired T790M resistance mutations and remain investigational. However, the FDA is currently considering an application for rociletinib.

In those with ALK rearrangements, ceritinib or chemotherapy should be utilized in the second-line setting, based on prior response to crizotinib. A number of other next-generation ALK inhibitors are also under development but were too early in the research process to be included in the guideline.

In the third-line setting, the guideline recommended treatment with erlotinib for patients who have not received erlotinib or gefitinib. In this setting, there was a lack of evidence to support the administration of chemotherapy.

The guideline remained unclear on the optimal role for ramucirumab in patients with NSCLC. In December 2014, the FDA approved ramucirumab in combination with docetaxel for the treatment of patients with metastatic NSCLC whose tumor has progressed during or following treatment with platinum-based chemotherapy. This decision was based on a 1.4-month improvement in OS with the addition of ramucirumab.

"The role for vascular endothelial growth factor inhibitor therapy in the second-line setting is not clear," the authors wrote. "Patients with EGFR or ALK genomic tumor aberrations or mutations are most appropriately treated with FDA-approved agents targeting those aberrations before receiving ramucirumab."

In addition to upcoming updates concerning the use of immunotherapy and third-generation EGFR inhibitors, the guideline lacked discussion on other agents in late-stage development, including necitumumab. The FDA is set to make a decision regarding a new drug application for necitumumab by the end of 2016. In July, ODAC informally recommended the drug's approval.

Masters GA, Temin S, Azzoli CG, et al. Systemic Therapy for Stage IV Non—Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update [Published online August 31, 2015]. J Clin Oncol. doi:10.1200/JCO.2015.62.1342.