Therapy Options in HR+/HER2- Breast Cancer - Episode 17

Optimizing Management of HR+/HER2- BC: Future Directions in Care

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Closing out their discussion on HR+, HER2- breast cancer, expert panelists share their excitement for further evolution in the treatment paradigm.


Hope S. Rugo, MD, FASCO: There are so many things going on in hormone receptor [HR]-positive disease. I’d like to spend our last few minutes finding out from each one of you what other things you’re looking forward to in metastatic disease and where we’re going. Do you want to start, Komal?

Komal Jhaveri, MD, FACP: There is a lot happening, including with established therapies, and we’re still trying to answer the question: What do we do with those therapies? What have we figured out? Should we continue those therapies, or should we swap them in our practice? There are many other targets; we covered PI3K and Akt inhibitors, mutant selective PI3K inhibitors at the interim clinic, so that would be a nice way to see [whether] we can overcome toxicity for these patients. We have talked about HER2 mutations and how ADCs [antibody-drug conjugates] might have a role even in those mutations. We did update the results from the SUMMIT trial [NCT01953926] for neratinib plus fulvestrant plus trastuzumab for our HR+, HER2-, HER2-mutant population but the triplet did show a progression-free survival of 8.2 months. Hopefully, we’ll have 2 kinds of therapies with HER2-mutant disease, especially [patients with] alveolar cancer where this is prevalent in about 15% to 16%. A lot needs to be done; we have newer ways of trying to tackle these resistance mechanisms. Now we’re going to try [to] focus on how we can optimize them, how we can sequence them, how we can use rationally scientific-based design, combination therapies of an ADC with another agent, whether it be IO [immunotherapy] or a PARP inhibitor with ADCs. All that work is very exciting.

Hope S. Rugo, MD, FASCO: Indeed. Mark?

Mark Pegram, MD: I’m still excited about [ADCs]. We’ve seen all the data of the potential of this class of drugs at this ASCO [American Society of Clinical Oncology conference], particularly in breast cancer and particularly with cytotoxic payloads. But ADCs need not be restricted to cytotoxic payloads, and that’s what I find most exciting right now as we’re working on some [ADCs] that have immunological payloads instead of cytotoxic payloads. One of the studies we’re doing at my institution [Stanford Cancer Center, California] is using a toll-like receptor 7/8 agonist immunologic payload conjugated to an HER2 antibody backbone. Those were in Edgar Engleman’s [MD] lab at Stanford [University] and they have a start-up now called Bolt sponsoring that trial and it’s ongoing; we had our investigator here at this ASCO and it’s moving forward. The other molecule that’s really intriguing to me is from Mersana [Therapeutics], and we’re about to open their phase 1 first-in-human trial of an HER2 antibody conjugated to a STING agonist payload. This is a small molecule cyclic dinucleotide that causes dimerization of STING that then interacts with TBK1, which phosphorylates IR3 transcription factor that turns on the expression of type 1 interferons as the activation of human innate immunity through the STING pathway. To confine that to tumor cells with [ADC] is exciting. The trials so far have been disappointing, because if you try to activate STING systemically, it’s too toxic; you get too many autoimmune phenomena [adverse] effects. If you try to do intratumorally, the pharmacokinetics are not favorable, especially with small molecule cyclic dinucleotide derivatives. It’s just like getting sub-Q [subcutaneous] injection in many of those cases; it diffuses too rapidly and is cleared too quickly by the kidneys. So, defining that to just the tumor cell population could finally make some headway in the concept of STING agonist therapeutic approaches; I’m really excited about it.

Hope S. Rugo, MD, FASCO: That’s great—very cool new approaches.

Anne O’Dea, MD: Not to take away from anything that anyone said, because those are all very exciting areas, [but] I’ll just make a very quick general comment. I feel like in this ASCO more than ever we’ve seen more real-world data, more patient-reported outcomes. As a person who’s focused a lot on breast cancer survivorship, I think when we look at quality of life and how that is becoming such an important aspect, we’re getting real data where quality of life may be the decision for us about which agent we choose. Overall, I’m really encouraged to see that. I’m also very encouraged that the real-world data may be more representative of the patients we see, more inclusive. That is a wonderful advancement.

Hope S. Rugo, MD, FASCO: I was really pleased to have the disparities discussions and the poster discussion today; it was really very interesting and, to our viewers, if you can see those discussions, they are quite interesting.

Mark Pegram, MD: That came up in the Q&A during the oral breast cancer session [CROSSTALK] and the planning session, so it’s finally getting the attention it deserves.

Hope S. Rugo, MD, FASCO: Aditya, the final word?

Aditya Bardia, MD, MPH: I agree with what’s been said. There is a lot of interest and excitement related to [ADCs] and they are moving earlier with the idea [of] can we prevent metastatic disease? In the neoadjuvant setting, it’s very exciting because not only can you monitor response to [ADCs] but also understand biomarkers of response as well as resistance. In the neoadjuvant setting, the pretreatment biopsy can be utilized to understand predictive biomarkers, and then the surgical specimen—if there’s still residual disease—can be utilized to understand mechanism of resistance. So, for sacituzumab govitecan at ASCO 2022, the results of NeoSTAR [NCT04230109] were presented by Laura Spring, MD, and you could see the response rate even with single-agent sacituzumab govitecan. There will be ongoing work to understand biomarkers of response and resistance. Similarly, with trastuzumab deruxtecan, it’s being evaluated in the neoadjuvant setting, not only for HER2+ disease but also HER2-low [HR+] breast cancer in the neoadjuvant setting in the TALENT trial [NCT04553770], so I look forward to those results.

Hope S. Rugo, MD, FASCO: These are really exciting, and I think the work Laura Spring, MD, presented with your neoadjuvant sacituzumab trial is quite intriguing with the pCR [pathological complete response] just for sacituzumab, 4 cycles of around 43%.

Aditya Bardia, MD, MPH: 30%.

Hope S. Rugo, MD, FASCO: Forty-three percent was some subgroup. Anyway, it’s always stage-based etc but really interesting. We’re all looking for those drugs, these [ADCs] to go in and there are a lot of postneoadjuvant trials also, either ongoing or planned. We’ve had a great time talking about this, I think. It’s a great group and you all have so much information to share. We have so much excitement from ASCO 2022 and looking forward. Thanks to all of you for participating and I appreciate your final thoughts. Thank you for joining us. We hope you found this OncLive Peer Exchange® discussion to be useful and valuable to the treatment of your patients with [HR+] metastatic breast cancer, with not only a view to today but also to the future. Thank you.

Transcript edited for clarity.