Audio: CRESTONE: Initial efficacy and safety of seribantumab in solid tumors harboring NRG1 fusions - Daniel R. Carrizosa, MD @DCarrizosaMD @AtriumHealth #ASCO22 #OncoTwitter

Audio: CRESTONE: Initial efficacy and safety of seribantu...

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CRESTONE was an international multi-site study looking at the use of Seribantumab a monoclonal antibody to HER3 in the treatment of patients with solid tumors that harbor and NRG1 fusion. The study actually is looking at patients that have been treated with at least one form of therapy prior to coming into study.

And they must be adults that have a solid tumor that harbors an energy, one fusion that is found locally. The patients then receive Seribantumab weekly until they either have progression or they have unacceptable toxicities. The study actually presented 2 different things, both the safety and the efficacy in this interim analysis where the data was stopped in April of 2020.

Safety used patients, both in the study and in earlier studies, and it looked at the factor that the majority of the adverse events caused by Seribantumab were actually mild grade 1 or grade 2. And, usually very tolerable. They included diarrhea and rash. And no patient actually came off study due to adverse events from the drug, and there were no associated deaths from the drug.

The study actually purported investigator assessed overall response rate. And that was 33% in the 12 of valuable patients. The majority of those patients actually had non-small cell lung cancer with one patient with pancreatic cancer in the non-small cell lung cancer group. The overall response rate was slightly higher at 36%, and more importantly, they had 2 complete responses and 2 partial responses.

This study actually showed the first complete responses in any patient treated. With an air energy, one fusion over 90% of patients had some type of disease response to the drug and therefore it was felt that it actually had a very good efficacy and the safety was quite tolerable. Therefore, the study was hopefully gonna show the potential for this drug to be a new treatment for patients with NRG1 fusions.

One of the most common questions people ask me about the study is how common are these NRG1 fusions? And these oncogenic alterations are quite rare. We see them about 0.2% of patients but their current have 10 different types of solid tumors. So, it is something that we should be looking for. These patients also don't seem to do as well.

Patients a large international registry study on looking at mainly lung cancer. Patients showed that these patients did not respond to standard therapies like chemotherapy or immunotherapy and had worse outcomes. Beyond that patient people also question and ask about how people receive the drug and that is done weekly through intravenous method and whether it was very tolerable and the study did show great tolerability.

The data from CRESTONE is in an intermediate analysis. The data's not gonna effectively change a standard of care at this point. But I think the important part that's come out of it is that a, NRG1 fusions are targetable few oncogenic alterations that we could actually hopefully have treatments for in the future.

And the other thing that's important is that these fusions are usually found with RNA-based next-generation sequencing. So, this actually helps again solidify the factor that we need to be thinking about all of these potential oncogenic alterations and doing the best next-generation sequencing we have.

Which should include RNA-based sequencing. This will help us find things like NRG1 fusions, as well as NTRK fusions and other things. And this will help with the personalized medicine for our patients and for the treatments that they can receive.

The next step for this research is the actual continuation of the study. And to get more patients, the main arm of the study cohort, one that is potentially registrational cohort, is trying to get at least 55 patients. And there's still more patients to be enrolled into the study so that we can get finalized data and see how well this drug actually works.

When we think about what's important about this data is again, the factor that we have, new fusions or oncogenic alterations that we can start targeting, and that we are having new therapies that might be able to make our patients have better outcomes and live longer. On top of that, it helps show that we are trying to find new avenues for therapy and that we need to do.

New and up-to-date sequencing with RNA based sequencing so that we can actually go ahead and find what we need to find and help our patients as much as we can.

Daniel R. Carrizosa, MD, MS is a board-certified medical oncologist and hematologist, specializing in Head and Neck and Lung Cancer at Atrium Health Levine Cancer Institute. In this interview, he speaks about the ASCO 2022 Abstract - CRESTONE: Initial efficacy and safety of seribantumab in solid tumors harboring NRG1 fusions.


Origins:

NRG1 fusions are uncommon oncogenic drivers reported in 0.2% of all solid cancers. These fusions cause ERBB3/HER3 overactivation, which promotes tumor development and cell survival. There are no authorized targeted treatments for NRG1 fusion-positive malignancies at the moment. Furthermore, patients (pts) with NRG1 fusion tumors have poor prognosis with traditional therapy. Seribantumab is a completely human anti-HER3 IgG2 monoclonal antibody that inhibited tumor growth in preclinical NRG1 fusion mice. We share preliminary clinical results from the CRESTONE research here (NCT04383210).

Methodology:

CRESTONE is a global, multicenter, open-label Phase 2 study of seribantumab in adults with locally advanced or metastatic solid tumors with NRG1 fusions. The RP2D was established as a 3g once weekly (QW) intravenous dose administered until treatment cessation criteria were reached after a dose range period. Cohort 1 will include at least 55 patients who have had at least one prior therapy and are new to ERBB-targeted therapy in the expansion phase. Patients who have previously been treated with ERBB-targeted treatments and/or tumors with other molecular changes will be enrolled in exploratory cohorts 2 or 3. The primary endpoint is the objective response rate (ORR) as determined by an impartial central review in accordance with RECIST v1.1. The authors present preliminary data from cohort 1 patients who received seribantumab 3g QW with investigator (INV)-assessed response following RECIST v1.1.

Outcomes:

By JAN-13-2022, 12 patients in cohort 1 had received seribantumab 3g QW. The median age was 65 years (range 44-76), 67% were female, and the median number of prior therapies was one (range 1-5). Local next-generation sequencing testing revealed 5 distinct NRG1 fusion partners (ATP1B1, CD74, ITGB1, SDC4, SLC3A2) in 92 percent (11/12) of the patients. The confirmed ORR was 30% among 10 patients evaluated for INV-assessed response, while the illness control rate was 90%. (1 complete response, 2 partial responses, 6 stable disease, 1 progressive disease). 58 percent (7/12) of patients remain on study treatment, including two patients with NSCLC who obtained objective responses with continuous durations of response ranging from 6 to 8.5 months. There were no drug discontinuations or dose reductions with seribantumab 3g QW. Across all cohorts (n = 29), the most frequently reported treatment-related adverse events (TRAEs) (20%) were diarrhea (38%), fatigue (34%), and rash (24%), all of which were grade 1 or 2. There was one grade 3 TRAE of vomiting; there were no grade 4 or 5 TRAEs. Efficacy analysis is in underway, and new efficacy results from evaluable patients in cohort 1 will be presented.

Inferences:

Seribantumab elicited persistent responses in advanced solid tumors with NRG1 fusions and has a favorable safety profile, according to preliminary findings. These findings support the ongoing CRESTONE study's use of seribantumab in NRG1 fusion-positive solid tumors.