Manish R. Patel, DO, further discusses next steps for entrectinib, as well as the need for genetic testing to identify uncommon gene rearrangements in GI malignancies.
While entrectinib (Rozlytrek) is a well-tolerated agent that has shown efficacy in numerous tumor types, including NTRK-positive gastrointestinal (GI) cancers, Manish R. Patel, DO, indicated a need for broad molecular testing in order to identify patients with NTRK rearrangements.
In August 2019, the FDA granted an accelerated approval to entrectinib for the treatment of adult and pediatric patients 12 years of age or older with solid tumors who harbor an NTRK fusion. The agent has since been approved for the treatment of adults with ROS1-positive, metastatic non–small cell lung cancer (NSCLC). The approval was based on the integrated analysis of several studies, including the phase 2 STARTRK-2, the phase 1 STARTRK-1, and the phase 1 ALKA-372-001 trial.
At the 2020 ESMO World GI Conference, updated results were presented on the integrated analysis. The analysis included over 500 patients with locally advanced or metastatic NTRK fusion–positive solid tumors. Some of the tumor types include breast cancer, cholangiocarcinoma, colorectal cancer, gynecological cancer, NSCLC, pancreatic cancer, and thyroid cancer.
The updated findings continued to demonstrate encouraging response rates and duration of response (DOR), as well as a tolerable safety profile with entrectinib in this patient population.
“The data that we have seen so far suggest that entrectinib in NTRK fusion–positive patients is at least as effective as any of those other treatment options and comes at a lower cost of toxicity,” said Patel. “If we can identify the patients who have these rearrangements, we can really offer them something that's probably at least as good as what we currently have available and come at lower toxicity.”
In an interview with OncLive, Patel, a hematologist/oncologist and associate professor of medicine within the Division of Hematology, Oncology, and Transplantation at the University of Minnesota, further discussed next steps for entrectinib, as well as the need for genetic testing to identify uncommon gene rearrangements in GI malignancies.
OncLive: Could you provide some insight on the role of entrectinib in GI cancers?
Patel: Entrectinib is an inhibitor of NTRK1/2/3 kinases, as well as ROS1 and ALK. In patients who have these abnormalities, entrectinib is a quite effective and well-tolerated option that virtually all patients with GI malignancies can tolerate. It certainly has a place. Now, that being said, these gene rearrangements are fairly uncommon in GI malignancies, but for the right patient who has these mutations, entrectinib represents a really good option.
What is the mechanism of action with entrectinib and the rationale for using it in GI cancers?
It's a TKI and it also has activity in the central nervous system (CNS), so it is not particularly unique in its mechanism of action [when compared with] other TKIs. Its specificity seems to be pretty unique to NTRK, ALK, and ROS1 and doesn't have a lot of other inhibitory action on other tyrosine kinases. Specific to GI malignancies, there's really nothing in particular that targets GI malignancies. It has been approved for NTRK fusion–positive patients of other tumor types, as well as for ROS1–rearranged lung cancer tumors.
Could you discuss the design of the integrated analysis? Which patients were included in the studies?
The data for this study were taken from the initial phase 1 studies of entrectinib in the ALKA-372-001 and the STARTRK-1 studies, which included patients with all solid tumors with NTRK-, ROS1-, or ALK-rearranged tumors. The phase 2 STARTRK-2 study, which was also a multicenter, global basket study that included all solid tumors with NTRK-rearranged tumors, had baskets for NSCLC patients with ROS1 and ALK rearrangements, and then a separate basket for patients who were NTRK fusion–positive.
This analysis includes patients who are NTRK fusion–positive who also have GI malignancies. There were a total of 74 patients with NTRK fusion–positive tumors of all different types. In the pooled analysis of all 3 studies, 12 patients had GI malignancies. In particular, 11 of those 12 patients were taken from the phase 2 STARTRK-2 study, but there were 3 additional patients from the phase 1 dose-escalation studies. There was also a safety analysis that was done on patients of all tumor types and gene rearrangements, including 16 patients with GI malignancies.
The primary end point of this study was ORR and DOR. For secondary end points, we're looking at progression-free survival. We did have a plan to look at intracranial objective response and DOR. However, in GI malignancies, central nervous system (CNS) metastasis is relatively uncommon—we didn't actually have any patients in the study with brain metastases. Then, we also looked at the safety and tolerability.
Regarding efficacy, what findings were uncovered?
One thing that we could say for sure is that the vast majority of patients had some degree of tumor regression. It was not particularly suited to one particular tumor type over another. There were patients with colorectal cancer, cholangiocarcinoma, and pancreatic carcinomas in the cohort. The ORR was 50%, and the median DOR was 12.9 months. Again, the numbers for each individual tumor type are relatively small, but this gives you a pretty good overview that the drug is effective in patients with NTRK fusion–positive tumors and yields a pretty durable response.
In regard to safety, were there any signals observed with entrectinib that could be noted?
Nothing that was unexpected. The NTRK gene is known to be associated with neural networks. Some of the adverse effects (AEs) that we expected to see were things like dizziness and taste change. Those were clearly seen in this study and in others, as well. There wasn't a lot of unexpected toxicity. Overall, the toxicity that we saw was very mild. The vast majority of [AEs] were grade 1/2 and resolved or improved with either dose reduction or brief dose interruptions.
In fact, only one patient in this analysis required discontinuation from treatment, but even looking at the 500 patients in the overall safety population, the vast majority of the AEs were grade 1 or 2. There were 2 treatment-related deaths that were seen. It was not clear from those whether they were related to entrectinib.
What are the clinical implications of these findings? Are there any next steps planned?
The study is going to continue to enroll patients with the plan of enrolling several more patients over the next 1.5 years to get more data. It's difficult to make a clear conclusion based on an analysis of 12 patients. However, the data are consistent with what we've seen with entrectinib with other tumor types with NTRK fusion–positive tumors. This tells us that we really need to screen patients to determine which ones have these NTRK rearrangements because we can offer them a very effective treatment. As it relates to GI malignancies, broad molecular testing is not done beyond KRAS and BRAF. The data presented here suggest that we should include NTRK in patients with GI malignancies and other tumor types so that we can identify these rare patient populations that have a very effective treatment option.
Is there anything else that you would like to highlight regarding these studies or the analysis?
Again, the main take-home point from this study is that we need to do more molecular testing for these patients so we can identify them. Most of the patients with GI malignancies have a few lines of FDA approved treatment that come at the risk of a fair bit of toxicity.