Targetable Mutations in NSCLC: More Testing Needed!


Diagnosis of adenocarcinoma of the lung, a major subtype of non-small lung cancer (NSCLC), nowadays triggers mandatory testing of tumor tissue for alterations in four genes: EGFR, ALK, ROS1, and more recently, BRAF. If present, these alterations predict sensitivity to specific targeted drugs approved by the U.S. Food and Drug Administration (FDA) that work better and often longer than standard chemotherapy, and are better tolerated.

However, there are many more targetable/actionable genomic alterations (also known as “drivers”) in NSCLC. This blog post will briefly discuss most of them, with the goal of promoting molecular testing for more than the four “usual suspects” mentioned above. Some patients with these alterations may benefit from FDA-approved drugs or from enrollment in clinical trials that are testing additional drugs and drug combinations.

Molecular alterations in NSCLC for which there are FDA-approved treatment options

EGFR: EGFR is mutated in 10% of Caucasian patients with NSCLC and in 25% of Asian patients. EGFR mutations are more frequent in non-smokers. Most mutations in EGFR are either deletions in a portion of the gene called exon 19, or a mutation known as L858R in exon 21; these two account for 90% of all EGFR mutations. Rare mutations are found in exons 18 or 20. There are four FDA-approved drugs that target EGFR mutations (erlotinib/Tarceva, geftinib/Iressa, afatinib/Gilotrif and osimertinib/Tagrisso), and more drugs are being investigated in clinical trials. Mutations in exon 18 respond better to afatinib than to erlotinib or gefitinib, while alterations in exon 20 may respond better to osimertinib, and likely to some drugs currently in trials (nazartinib/EGF816 and poziotinib).

For a patient who receives EGFR-targeting drugs, it is almost inevitable that these medications will eventually stop working. When this happens, it is very important to conduct new mutational testing to determine the mechanism of resistance to these drugs. Testing can be performed on a biopsy of a resistant lesion or a liquid biopsy (via blood test). Several known molecular alterations lead to resistance, and while I will not go into details here, many of these can be addressed by using relevant targeted drugs.

ALK: The gene ALK is involved in “chromosomal translocation” in which it becomes fused with another gene, EML4. The frequency of EML4-ALK translocation is about 5% to 8% in NSCLC and is much higher in non-smokers, accounting for 22% of mutations found in non-smokers.

Crizotinib (Xalkori) is the FDA-approved first-line treatment for tumors with ALK rearrangements. and ceritinib, alectinib, and brigatinib are used for treatment of ALK-positive cancers that develop resistance to prior treatment with an ALK inhibitor. Lorlatinib may be approved soon.

ROS1: This gene is involved in translocations in about 1% to 2% of NSCLC cases. ROS1 is closely related to ALK, and crizotinib is the FDA-approved drug for this subtype. Other ALK-targeting drugs that are already approved for the ALK subtype (ceritinib and lorlatinib) have shown excellent activity in the ROS1 subtype as well. Entrectinib (RDX-101) and PF-02341066 are also in trials for ROS1-translocated NSCLC.

BRAF: This mutation is found in 3% to 4% of NSCLC cases and is strongly associated with smoking history, unlike the three mutations above. V600E is the predominant type of BRAF mutation, and its presence in tumors is associated with a very high rate of response to the combination of dabrafenib (Tafinlar) and trametinib (Mekinist), which was approved by the FDA in June 2017.

Molecular alterations in NSCLC for which drugs are available in clinical trials

MET amplification: A high number of copies of the MET gene is found in 3% to 7% of newly diagnosed NSCLC cases. It is a more frequent alteration (21%) that drives resistance to EGFR inhibitors in EGFR-mutant cancers. Drugs in trials for patients with amplified MET are crizotinib, cabozantinib, tivantinib, glesatinib (MGCD265), and INC280.

MET exon 14 skipping: This particular form of MET alteration (METex14) results in production of a potentially overactive MET protein. It is encountered in 3% to 4% of NSCLC cases, more often in older patients, and is not particularly characteristic of non-smokers. Of interest, a different type of lung cancer, pulmonary sarcomatoid carcinoma, harbors MET exon 14 skipping in 20% to 30% of cases. About 20% of METex14 cancers also contain a high number of copies of METex14. A number of drugs that might work against METex14-positive tumors are available through trial enrollment; these include crizotinib, capmatinib, tepotinib, and merestinib.

HER2: Mutations in this EGFR-related gene are found in 2% to 5% of cases of adenocarcinoma of the lung, more often in Asian patients, and mostly in non-smokers. The most common HER2 mutations are insertions in exon 20. The drugs dacomimitinb, neratinib, and pyrotinib are being tested in trials for HER2-positive NSCLC, and the EGFR-targeting drug afatinib could also be used for this subtype.

RET: This gene is altered in 1% to 2% of NSCLC cases and tends to form paired rearrangements with one of at least five other gene “partners.” A number of drugs, such as cabozantinib, vandetanib, alectinib, LOXO-292, BLU-667, and RXDX-105 are being tested against such tumors in clinical trials.

NTRK: The frequency of gene fusions/translocations involving the NTRK gene is estimated to be anywhere between 0.1% and 3.3% in NSCLC cases that have no other identifiable mutations. Drugs that are relevant to treatment of this subtype are entrectinib (RXDX-101) and larotrectinib (LOXO-101), which are both available in trials and have already been shown to have very good activity, including in disease that has metastasized to the brain. There are also relevant trials with other investigational drugs, like DS-6051b, TSR-001, and more.

Why and where to get testing?

29% to 45% of NSCLC patients may have targetable mutations, with EGFR, ALK, and ROS1 alterations accounting for only 16% to 20%. This provides a strong rationale for testing of multiple mutations in each patient, which is not yet mandated in National Comprehensive Cancer Network (NCCN) guidelines. However, the NCCN “strongly advises broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available or to appropriately counsel patients regarding the availability of clinical trials.”

 Numerous providers offer mutational testing, and some of these tests are covered by health insurance plans, which should be discussed with the treating oncologist. Just recently, a possibility of getting free mutational testing for some cancer patients was announced. Fifty hospitals will be able to order testing from Strata Oncology, and while this test is not specific for NSCLC, it will cover many of the rare mutations. The Strata testing process will include matching patients to potentially relevant clinical trials.

Remember: “Broad molecular profiling is a key component of the improvement of care of patients with NSCLC.” –NCCN guidelines