Summary Recommendations

Pathological Reporting and Molecular Subtyping:

Diagnosis made according to WHO classification

Category 2A

If non-squamous in histology (category 1), never or former light smokers squamous histology (level 4, A), small biopsy specimen or mixed histology, testing for EGFR activating mutations and ALK testing are recommended.

Category 1 (non squamous)

Level 4, A (never or former light smokers squamous)

The workgroup supports detection of ALK translocation by fluorescence in situ hybridization (FISH) as standard, however immunohistochemistry (IHC) and RT-PCR based methods can be used if validated and qualified.

Category 2A

If possible, parallel testing for molecular aberration is preferable to avoid delay in treatment.

Workgroup consensus

ROS1 testing can be considered.

Category 2A

The workgroup also supports NCCN endorsement of broader molecular profiling with the aims of identifying tractable mutations and informing patients on availability of clinical trials

Category 2A

Rebiopsy at disease progression should be considered

Category 2A

First line EGFR mutation positive:

Either of the EGFR-TKI gefitinib, erlotinib or afatinib should be considered in the treatment of advanced NSCLC harboring EGFR sensitizing mutations.

Category 1

Should the mutation be discovered in the midst of first line treatment, the systemic therapy can be interrupted or first line chemotherapy can be completed prior to starting EGFR-TKI.

Category 2A

First line ALK mutation positive:

Clinical Trials

Category 2A

Consider crizotinib as first line treatment for ALK gene rearranged advanced lung cancer. The workgroup recommends a discussion with patients on the cost implications of this option prior to mutational testing

Category 1

May switch to ceretinib if intolerant to crizotinib

Category 2A

First line chemotherapy, driver mutation negative

In fit patients, platinum doublet chemotherapy is recommended in the first line treatment of advanced NSCLC.

Category 1

In view of better outcomes with the use of pemetrexed in non-squamous histology and in considering cost effectiveness, the workgroup is of the opinion that pemetrexed/platinum chemotherapy is preferable in the first line treatment of non-squamous advanced NSCLC.

Workgroup consensus

Addition of bevacizumab to platinum doublet is an option in non squamous histology

Category 2A

The use of bevacizumab as well as pemetrexed is limited to those non squamous in histology.

Category 2A

There is insufficient evidence to support the use of cetuximab for which the workgroup unanimously does not recommended in this setting.

Workgroup consensus

Maintenance Chemotherapy:

In patients with good performance status of 0-1, continuation of pemetrexed (is recommended in non-squamous NSCLC if stable disease or response is seen following induction chemotherapy.

Level 1, B

In patients with non squamous histology and good PS 0-1, should first line chemotherapy be non-pemetrexed based, then switch maintenance to pemetrexed can be considered (Level 1, B).

Level 1, B

In patients with all histology, switch to erlotinib can be considered (Level 1, B) however the workgroup recommends this only if a sensitizing EGFR mutation is detected (workgroup consensus)

Level 1, B

Workgroup consensus

Second Line Chemotherapy:

The workgroup committee recommends consideration of clinical trials.

Workgroup consensus

Docetaxel or pemetrexed (restricted to non squamous in histology) can be considered in fit patients as second line treatment of advanced lung cancer.

Level 1, B

Subsequent Lines of Chemotherapy:

The workgroup recommends first the consideration of clinical trials.

Workgroup consensus

Erlotinib can be considered in the treatment of advanced lung cancer beyond second line chemotherapy in patients with unknown EGFR status or EGFR WT who have not received EGFR TKI.

Level 2, B

Given the burgeoning pipeline of novel therapeutics addressing either distinct genetic drivers or resistance mechanisms, molecular profiling for actionable alterations either from archival tissue, or a repeat biopsy is also a reasonable consideration.

Workgroup consensus

LoE, Available level of evidence