Treatment Resistance Due to Gene Mutation

Luis Raez, MD: We repeat molecular profiling when patients progress, especially patients who have fusions like ALK, ROS, and NTRK. We do that because there is very good documentation that these fusions suffer mutations. These mutations are creating resistance to the tyrosine kinase inhibitors. In the specific case of ALK, we have a whole library of well-known resistance mutations that arise while these patients are treated with tyrosine kinase inhibitors. We learned that from the ALK and ROS1 patient history, and now we’re learning the same of these patients treated with larotrectinib or entrectinib. By the time we had all these data published, we had already seen that several of these patients treated with larotrectinib or entrectinib developed resistance mutations. For that reason, it is necessary to document the resistance mutations to try to find the next treatment.

This is automatic in the case of ALK resistance mutations, because in the case of ALK we already have 5 FDA-approved agents and 2 or 3 drugs being researched. If you have a patient with an ALK alteration who develops resistance, you have so many options for him. We really need to retest. The question is how you retest these patients. It depends. If it’s convenient, you can perform a tissue biopsy. For example, if the patient develops a new, single liver metastasis and you are going to use some form of local therapy, maybe it’s convenient to take a biopsy before you administer local therapy like stereotactic radiation or radiofrequency ablation.

If you don’t have a large volume of tumor, maybe the easiest method is to use a liquid biopsy, sequence DNA in the blood, and try to identify the resistance mutation and get more information from these patients. That’s why I think repeating the genomic profiling of the patient is very important. Of course, it is more focused. However, we know that the patients are going to develop mechanisms of resistance, such as MET amplification. That’s why it’s very important to do the genomic profiling. That is a controversial topic. A lot of people will say, “Oh, we are not ready. Why are you doing that? Just put them on chemotherapy, and forget about this.” But this is something that is evolving as we speak, and when we are doing research, it’s very important that we repeat the molecular profiling for all these genetic fusions in lung cancer.

For NTRK-targeted therapies, we already have some resistance mutations that have been well described, not only in lung cancer but also arising in patients with other cancers. We have treated a lot of fibrosarcomas and other types of tumors that carry these NTRK fusions. That’s why we have been developing an agent called LOXO-195. Other companies have other potential agents that can help us treat these patients to overcome resistance. There are already presentations of LOXO-195 that show the drug is able to rescue patients with resistance mutations. That is why I’m very optimistic about the future. At least we now have a second-generation NTRK inhibitor that will be able to rescue patients who fail the first line of defense.

The role of next-generation sequencing [NGS] is very important because that’s what we use now. Everybody agrees that we have to use next-generation sequencing and DNA testing at least once in every patient with lung cancer. There is a little bit of controversy about using NGS at progression. It’s important to understand that because of NTRK, especially NTRK3, patients have different variants that may not be captured by the DNA sequencing. It’s necessary that we add the RNA sequencing to complement that and be able to discover the genetic alterations that we cannot discover when we analyze only DNA.

We know that we can use, in specific cases, immunohistochemistry. The pan-TRK antibody seems to be good. As I said, we know more or less which genetic alteration we’re going to find. If I know for certain, for example, that this is a patient subset with a high incidence of NTRK3 genetic alteration and secretory breast carcinomas, I can pinpoint and look for that genetic alteration, and I don’t have to worry about all the other NTRK fusions or genetic alterations.

That’s why there is a little bit of room to be more flexible and incorporate pan-TRK immunohistochemistry. I understand, you cannot use next-generation sequencing so often because it’s a very expensive test. However, the cost is hopefully going to go down like everything else in science. It’s amazing. We will be able to use it more often, but until then, we have to find other ways to work. Certainly, we would love to see accurate pan-TRK immunohistochemistry so that all of us can use it in any part of the United States in any small hospital in the most cost-effective way.

Transcript edited for clarity.

Case: A 67-Year-Old Man With NTRK Fusion-Positive Metastatic Non-Small Cell Lung Cancer

Initial presentation

A 67-year old man presented with a 2-month history of cough and dyspnea on exertion

PMH/SH: hypercholesterolemia, never smoker

PE: right-sided wheezing on auscultation

Clinical workup

Labs: WNL

Chest X-ray showed a right-side mass ~2.5 cm

Chest/abdomen/pelvic CT showed a 2.7-cm solid pulmonary lesion in the right lobe, ipsilateral mediastinal lymph node involvement

CT‐guided core needle biopsy of the lung lesion and lymph node revealed lung adenocarcinoma, grade 3

Contrast‐enhanced MRI of the head showed a small lesion (0.6 cm); indicating CNS metastasis

Molecular and genomic testing:NTRK+, BRAF-, EGFR-, ALK-, ROS1-,KRAS-, PD-L1 0%

Stage T1cN2M1b; ECOG PS 1

Treatment and Follow-Up

Larotrectinib 100 mg PO BID was initiated; treatment was well-tolerated

Stereotactic radiosurgery of the brain was deferred due to location and increased risk of post-operative morbidity

Imaging at 2 months showed stable disease; sustained response upon follow-up

Imaging at 18 months showed decreased size of pulmonary and brain lesions

Repeat genomic testing: NTRK+