Updated NCCN Guidelines Expand Targeted Therapy Options for Patients with Metastatic NSCLC

Updated guidelines from the National Comprehensive Cancer Network (NCCN) on the management of patients with metastatic non–small-cell lung cancer (NSCLC) reflect the addition of osimertinib (Tagrisso) as a first-line treatment option for patients with an EGFR-sensitizing mutation, and as subsequent therapy for patients with a T790M resistance mutation whose disease progresses after treatment with another tyrosine kinase inhibitor (TKI).

At the 2018 NCCN Conference, Karen L. Reckamp, MD, MS, Co-­Director, Lung Cancer and Thoracic Oncology Program, City of Hope Comprehensive Cancer Center, Duarte, CA, discussed the latest developments in targeted therapy for metastatic NSCLC. Dr Reckamp was on the panel that developed the updated NCCN guideline.

“We have a growing list of oncogenic mutations and therapeutic options for patients with lung cancer,” she said. Oncogenic targets for which therapies are currently approved include EGFR, ALK, ROS1, and BRAF mutations.

The NCCN version 3.2018 guideline has multiple sections to guide the first-line treatment of patients with metastatic NSCLC, based on histologic subtype and the results of molecular testing, which is now recommended for all patients as part of the initial workup of patients presenting with metastatic NSCLC.

“We now have 4 drugs in the guideline for the first-line therapy of NSCLC—erlotinib, afatinib [Gilo­trif], gefitinib, or osimertinib,” Dr Reckamp told attendees.

Osimertinib Added to First-Line Options

Osimertinib has been added to the list of recommended TKIs in the updated NCCN guideline.

The double-blind FLAURA clinical trial compared osimertinib versus standard therapy with erlotinib (Tarceva) or gefitinib (Iressa) in patients with untreated, advanced NSCLC and EGFR mutation. The median progression-free survival (PFS) was 10.2 months with standard therapy versus 18.9 months with osimertinib (hazard ratio, 0.46; P <.001). Patients with or without central nervous system (CNS) metastases benefited similarly from osimertinib. An overall survival interim analysis demonstrated a trend toward improved survival with osimertinib. Grade 3 or 4 rash and liver function abnormalities were lower with osimertinib than with standard therapy.

Patients with sensitizing EGFR mutations who respond to EGFR-targeted therapy will have disease progression and secondary resistance.

The T790M mutation on exon 20 accounts for approximately 50% of acquired resistance to erlotinib. Osimertinib is approved for patients with NSCLC and T790M mutation when acquired resistance occurs.

“We believe that resistance will be quite different if people start using osimertinib as first-line therapy,” Dr Reckamp said.

Questions remain regarding the specific sequence of TKIs, and whether earlier-generation EGFR-targeting TKIs and chemotherapy will work after first-line treatment with osimertinib. Dr Reckamp indicated that a movement toward osimertinib in the first-line setting is taking place as a result of the FLAURA study data.

When NSCLC progresses with a first- or second-generation TKI, testing for T790M is recommended.

“At this point, we consider plasma testing equivalent to tissue testing if it’s positive…and can often save the patient a biopsy,” said Dr Reckamp. As subsequent therapy, the guideline lists local therapy to the metastatic site (including brain), osimertinib (category 1), or continued treatment with erlotinib, afatinib, or gefitinib. For an isolated metastasis, local therapy or continuation of erlotinib, afatinib, or gefitinib therapy are options.

“When there are multiple sites and multiple lesions, then it’s clearly time to change therapies,” she said. Treatments to switch to include osimertinib, if it has not already been used for T790M-positive disease, or to cytotoxic therapy, if the cancer is T790M-negative.

Beyond EGFR

In patients with NSCLC and ALK mutation, alectinib (Alecensa) has been moved up in the guideline to first-line treatment as the preferred therapy, based on the results of the ALEX clinical trial. In that study, alectinib was superior to crizotinib (Xalkori) on the end point of median PFS, with an even greater improvement in median PFS with alectinib in patients with baseline CNS metastases. The same CNS activity was seen with alectinib in the J-ALEX clinical trial.

ALK mutation
Resistance mutations may guide the sequence of therapy in patients with NSCLC and ALK mutation, although at this time testing for resistance mutations is not standard of care, said Dr Reckamp. Multiple drugs—including ceritinib (Zykadia), alectinib, and brigatinib (Alunbrig)—with excellent systemic and CNS activity are FDA approved in the postcrizotinib setting, and they are listed as treatment options in the guideline.

ROS1 rearrangement
For patients with ROS1 rearrangement, crizotinib is now listed as the preferred first-line therapy, with ceritinib as another option; if the disease progresses, cytotoxic therapy is recommended.

BRAF mutation
Specific treatment options for patients with NSCLC and BRAF mutation are now listed in the updated guideline—first-line therapy with dabrafenib (Tafinlar) plus trametinib (Mekinist), or with cytotoxic therapy.

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