Transcript
Hi, my name is Fadi Braiteh. I'm a medical oncologist with Comprehensive Cancer Centers of Nevada, in Las Vegas, Nevada. I do practice mostly solid tumors with a focus on thoracic and GI and breast malignancies.
I would like to introduce to you today the newest drug added to the armamentarium about anti-cancer treatment, Rozlytrek. Rozlytrek, entrectinib, is anNTRK inhibitor. NTRK is N-T-R-K, which is the gene coding for TrkA, TrkB, and TrkC protein, which are involved in certain malignancies.
The FDA approved the drug in any tissue, any malignancies, as long as the tumor has NTRK rearrangement, regardless which was the companion with NTRK. There is no companion assay to come with. Any CLIA-certified lab-based assay, NGS or others, can make the patient eligible for the treatment, and regardless of what line of therapy.
Entrectinib, for which the brand name again is Rozlytrek. As the name sounds, it's ROS1 -- you can hear that -- ROS1 inhibitor. It's FDA-approved as well in advanced non–small-cell lung cancer (NSCLC) which harbors a ROS1 rearrangement regardless of the companion molecule and regardless of what assay led to the diagnosis. There is no specific line of therapy to define it.
This is unique. In fact, to my best recollection, this is maybe the first time I'm aware that the FDA approved a drug on the same day for 2 different indications.
Why that? Because the studies that led to this accelerated approval -- again, it's contingent on further data to be presented later on -- it's a combination of about 54 patients with solid tumors with NTRK rearrangement and 51 patients with ROS1 rearrangements.
Those patients were enrolled on a series of phase 1/phase 2 studies, including STARTRK-1 and STARTRK-2 studies. The safety data that we're aware of is based on more than these 51 and 54 patients, based on 355 patients. The eligibility for the study is really to find the solid tumors with NTRK rearrangement.
Yes, it's not very high prevalence. It's very rare. It's in the range of 1% to 3% of the common solid tumors such as pancreatic cancer, colorectal cancer, 3% of the non small-cell lung cancer.
Having said that, there are certain tumors where the incidence is a bit higher, maybe 3% to 5% in thyroid cancer, for example. Then the probability goes even higher in other tumors, such as the MASC breast cancer, M-A-S-C, or some other subset of saliva gland secrete mammary like secretory salivary gland carcinomas.
In general, sarcoma has an incidence of 1%. Yes, we need to test 100 patients on average before we find one. Remember, this is not new to us. In the world of lung cancer, we have ALK rearrangement in the range of 4%. We have ROS1 in the range of 1%. We got to learn that these very rare molecular abnormalities are to be looked after so we can find them.
The data shows that since it was a single-arm cohort of patients, the endpoint was median overall response rate and median duration of response. The data showed us that around half of the patients, >40% of the patient, that achieve response by this criteria, which mean partial or complete response. There were a few patients who did actually achieve complete response.
What's interesting as well is the median duration of response was meaningful. In fact, 45% of the patient with solid tumor and NTRK rearrangement had a response that lasted at least a year.
Specifically, over 20% of the patient that entered the study had CNS disease. There were 4 patients with measurable disease by RECIST criteria. Three out of the 4 patient had CNS response, which speaks for the drug crossing the blood-brain barrier and being effective in controlling the disease.
When it comes to the ROS1 population, there was about 51 patients enrolled, all with NSCLC ROS1 rearrangement. The phenotype of these patients have a tendency to be younger, nonsmoker Asian woman like the other molecularly specific driven malignancies, but these patients were enrolled with the entrectinib or Rozlytrek as a ROS1 inhibitor.
Half of the patient, which is common in this patient population, had brain mets. In fact, we know about 20 to 40 patients with ROS1 NSCLC present with brain mets. When they progress, 50% of the time it's intracranial progression. That is what interests to find a drug that cross the blood-brain barriers.
In this patient population, we see that the response rate by modified RECIST criteria was about 78%, so about 8 out of 10 patients had at least partial response. In fact, there were subset of these patients, 12% of the 78%, who were actually complete responders.
When it comes to the CNS-specific disease, over half of these 51 patients almost were had CNS disease. There were only 7 patients with evaluable CNS disease. We can see that 5 out of these 7 had at least partial response in the CNS.
It's all good news. This has led to be accelerated approval, but again there are some caution. The most common adverse events that will happen to these patients are in the range of fatigue, GI toxicity, constipation, diarrhea, nausea, vomiting, dysgeusia, dysesthesia. There are a few other adverse events, such as visual changes, etc.
The reason these patients will go to the ER to be admitted as a serious adverse event are mostly respiratory symptoms. It can be up to the third of the patients will go with dyspnea, pulmonary embolus, pneumonia, fever, pleural effusion, etc.
There is a caution. Since the drug safety cohort is only 355 patients, we need to alert the healthcare providers that there are some unusual adverse events that can occur, although not very frequently, such as congestive heart failure. If you suspect the patient has or is at risk of congestive heart failure, run the appropriate testing and monitor this patient with serial echocardiogram.
There is the visual changes that can happen. It may interfere with activity of daily living. Definitely, you have to warn the patient about NTRK, N-T-R-K, being neurotrophic tyrosine kinase. There's other CNS symptoms, anywhere from cognitive impairment, mood changes. We mentioned the dysgeusia, dysesthesia, allodynia, etc.
Do be careful. Don't give it to women who may become pregnant or breastfeeding. There are other adverse events that are not very common, but we don't understand why, is like bone fractures. These bone fracture can happen not in areas of metastasis.
I didn't mention earlier the drug is approved for kids age of 12 or adults. Why? Because some of these diseases, such as the sarcoma and others, have high prevalence of NTRK rearrangement. These patients were allowed to be entered on the study.
I give an example. Infantile fibrosarcoma, almost 100% of these patient have NTRK rearrangement. The MASC that I mentioned earlier, 100% has as well NTRK rearrangement. This is important, that this drug be presented to the pediatric oncology groups because we can have pediatric patients who may benefit from this drug.
Last but not least, I want to highlight hyperuricemia, liver enzyme increase, QTc prolongation as some of these adverse events that can occur. Again, this is another drug that has an FDA approval without necessarily linking or restricting it to a histology. It's any solid tumor with NTRK rearrangement and the non small-cell lung cancer with the ROS1 rearrangement.
It's 2 indications, same molecule that were both approved on the same day. Again, this is accelerated approval based on overall or objective response rate and median duration of response. Further data to be provided from the sponsor later on confirming the sustainability of these results.
