Updates Informing the Management of NTRK+ NSCLC

Balazs Halmos, MD: Discussing the recent approval for NTRK fusion pathway lung cancers and tissue agnostic NTRK fusion-positive cancers in general, for entrectinib, again, we have a very active molecule here. The response rate is quoted in this study in the 60% range. When you look at the waterfall plots, practically all patients seem to derive some benefit. There’s documented CNS [central nervous system] activity, CNS responses, and durable responses as well. We’re looking at an active, highly potent, and well-tolerated drug that’s an excellent choice for our patients.

Lyudmila A. Bazhenova, MD: As I mentioned before, entrectinib and other NTRK tyrosine kinase inhibitors are generally well tolerated. We see some unusual adverse effects, which are due to inhibition of the TRK pathway. Those are dizziness, perioral numbness, and weight gain. The majority of adverse effects, however, are mild. Discontinuation of the drug due to adverse event is very rare.

I've seen similar adverse effect profiles with larotrectinib, which is another agent approved for NTRK-rearranged cancers. As with entrectinib, weight gain, dizziness, and perioral numbness are reported. Discontinuation rate is also very low with larotrectinib.

Jonathan W. Riess, MD: When considering data from basket trials and whether I put more stock in efficacy in a particular tumor type or a drug's overall efficacy across all tumor types, I think the answer is that it depends. For NTRK fusion, when comparing non–small cell lung cancer to other tumor types, the non–small cell lung cancer group is so rare that you have to look at the activity in other tumor types as well.

What you see, whether it's larotrectinib or entrectinib, is (1) activity in non–small cell lung cancer, and (2) potent activity across other tumor types. For NTRK fusions, I put a lot of stock in the overall activity among multiple tumor types because it's so rare in non–small cell lung cancer, and within those patients, there is also activity.

It depends on the molecular aberration. Histology and tumor type are important, potentially in other genomic aberrations that drive cancer. Examples of this are dabrafenib and trametinib, with BRAF-mutated lung cancer and BRAF-mutated melanoma with V600E; they are very effective, but potentially less so when looking at colon cancer. That's a type where tumor histology and tumor type may be more relevant.

We're developing KRAS G12C specific inhibitor, and it’s early days, but we see more activity in non–small cell lung cancer, at least as an early snapshot. We need more patients, compared to other tumor types that we saw presented in the CodeBreak 100 trial at ASCO [the American Society of Clinical Oncology annual meeting] this year, where there were fewer responses in patients treated who did not have non–small cell lung cancer. It also depends on what the genomic aberration is.

For NTRK, I put a lot of stock in the basket trial and tumor type activity, on top of the activity we see in non–small cell lung cancer.

Balazs Halmos, MD: Nowadays, the ideal is to develop targeted drugs with CNS penetration, especially in my field of thoracic oncology where practically all patient subsets are at risk for CNS metastasis. If you think about it, tissue agnostic approval of these drugs—not all of the cancers would have a high likelihood of CNS metastasis, but many of them do. Lung cancer belongs to them, so it might not be an absolute must-have as a feature for this drug for every single patient, but for a very good subset, it is. It’s a nice thing to have, especially for patients with lung cancer. Some of these fusions occur in CNS malignancies as well. It’s important to have that additional characteristic, so I’m very happy with that.

NTRK fusion testing is recommended across the board for metastatic cancers with limited management options. All of us have to think about not just tissue specifically. For lung cancer, we have the mandate to test a number of actionable markers. NTRK is one of them. It’s a rare member, 0.3% or so, but an important one. Across tumor types, the clinicians need to remember that if you face a patient with an advanced cancer of probably any origin, that expanded molecular testing, including NTRK fusion testing and NRG fusion testing; that expanded profile will be beneficial to the clinician to feel comfortable guiding your patient to the best treatment choice and will definitely benefit your patient as well to make sure that all opportunities are exhausted and that they can reach the best life expectancy and best quality of life they can have, even in the face of an advanced malignancy.

Transcript Edited for Clarity