Expert: Updates for Zotatifin ER+/HER2- Breast Cancer Treatment

Douglas Warner, MD, chief medical officer at eFFECTOR, provides a comprehensive overview of zotatifin and its current status in a Phase 1/2 dose escalation and expansion study, with a focus on ER+/HER2- breast cancer. Zotatifin's mechanism of action involves suppressing key tumor-promoting proteins, such as estrogen receptor alpha and CDKs 2, 4, and 6, offering a promising approach in inhibiting breast cancer growth.

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Q: Can you provide an overview of zotatifin and its current status in the Phase 1/2 dose escalation and expansion study, particularly in the context of ER+/HER2- breast cancer?

Douglas Warner: Maybe the best approach is to take a step back and talk about zotatifin’s mechanism of action. We know that tumor growth is often driven by the overproduction of key tumor-promoting proteins, and zotatifin works by suppressing a network of some of these important tumor-promoting proteins. Some of these are particularly important in breast cancer. For instance, the estrogen receptor alpha, CDKs 2, 4, and 6, CDK4/6 inhibitors are major and important drugs in the treatment of ER+ breast cancer, and other proteins like cyclin D and E. Zotatifin works by inhibiting the production of these proteins, [and] the specifics of that is that it inhibits an enzyme called eIF4A that actually unwinds messenger RNA, and messenger RNA gets translated into protein, so it prevents messenger RNA from getting translated into these key proteins. The data that we presented is really 2 sets of data. One is an expansion cohort of zotatifin, combined with abemaciclib and fulvestrant, the trade names for those are Verzenio and Faslodex, and an expansion cohort where we looked at 20 patients and we've looked at safety and efficacy. Then we also combined zotatifin with fulvestrant in a dose escalation fashion to look at a dose schedule of every 2-week dosing.

Q: The data presented at SABCS included updates on the ZFA triplet cohort and resumed dose escalation cohorts. What were important takeaways from the interim data of the study?

Douglas Warner: In the triplet, this was a heavily pretreated cohort of patients. They had a median number of prior lines of therapy in the metastatic setting of 4. We found that the median PFS was 7.4 months, which is really a great outcome considering what the usual clinical course is in these patients, subsequent to having four prior lines of therapy in the metastatic setting. In the dose escalation, we found dose escalation was tolerable. We looked at 3 dose levels, 0.1 mg/kg, 0.14 mg/kg, and 0.2 mg/kg. We didn't see any dose limiting toxicities or serious adverse events, and we had 1 quite dramatic partial response at the first dose level in a heavily pretreated patient. We had 2 stable diseases in the second dose level and 1 in the third dose level. Once again, overall, in the dose escalation, these are heavily pretreated patients with a median of 4 prior lines of therapy in the metastatic setting in ER+ metastatic breast cancer. Overall, also, dealing with the safety of the triplet zotatifin combined with abemaciclib and fulvestrant was well tolerated. The large majority of events were mild and moderate.

Q: Based on the current available information, what insights can you provide regarding zotatifin's safety profile and how it might impact treatment decisions?

Douglas Warner: In combination with abemaciclib and fulvestrant, the 2 most common adverse events were low grade nausea and vomiting. That’s clearly something you want to manage, and we found that is very well managed with the sort of standard antiemetic prophylaxis.

Q: What potential implications do you foresee based on the interim data, and how might they impact clinical practice?

Douglas Warner: In ER+ metastatic breast cancer in earlier lines of therapy, particularly with so called CDK4/6 inhibitors, patients do quite well, but after these early lines of therapy, patients don't do as well, unfortunately. So, there's a lot of research in that area, looking at subsequent lines of therapy and how to improve clinical outcomes. I think going forward, we're going to look at adding zotatifin to backbone therapies like CDK4/6s and hormone therapies to improve outcomes in that setting. When we think about the development plan, I think there's a lot of opportunity in that area to help patients do better.

Q: How can pharmacists and health care physicians play a role in educating patients about emerging therapies like zotatifin for breast cancer?

Douglas Warner: The best approach is to look at clinical trials and clinical trials can be quite intimidating for patients and providers as well. A great resource can be patient advocacy groups. I know in the breast cancer area some of these patient advocacy groups have great websites, where they actually just walk through the basics of clinical trials. They decode clinical trials for patients. explain what they are, how they're administered, and so that's a great resource to overcome maybe some of the challenges with patient education about clinical trials, and ultimately the best, most comprehensive resources is clinicaltrials.gov, where if you want to look at specific therapies that somebody hears about a specific therapy, and they want to learn about trials, and if any trials are occurring in their area. Clinicaltrials.gov is a great resource for that.

Q: How can pharmacists and health care providers stay informed about ongoing developments in the study and zotatifin's progress?

Douglas Warner: Clinicaltrials.gov is a great resource to look at, where the studies with zotatifin are, where the sites are. I think, in general, we'd like to present our data at some of the key oncology conferences. This year, we presented at ASCO and San Antonio, so we can't predict where the data is going to be going forward. In general, I know pharmacists and health care providers, especially those who cover multiple different therapeutic areas, it's tough for them necessarily to stay abreast of what's going on in cancer congresses, but sometimes there are great websites and sources that just show highlights of the ASCO or highlights of San Antonio. That'd be a great way just to see potentially if we present data in the future, and it makes it to the highlight reel of these conferences.