Trial Data and Clinical Influences Shape Decision-Making Across the Breast Cancer Continuum

Individualized therapy is becoming increasingly important and possible across hormone receptor–positive, HER2-negative breast cancer subtypes, with recent trial data supporting switched endocrine therapy approaches, oral selective estrogen receptor degrader (SERD) regimen selection, and more, according to Komal Jhaveri, MD, FACP.

“Follow the [pivotal] trial [enrollment] criteria [when selecting patients for certain therapies], but also think about supportive management strategies to better help manage toxicities, so patients can stay on therapy and derive the intended benefit that we're offering these treatments for,” Jhaveri said in an interview with OncLive®.

In the interview, Jhaveri discussed updates regarding the use of CDK4/6 inhibitors for patients with hormone receptor–positive disease, how to balance the risk/benefit profile of inavolisib (Itovebi) for patients with PIK3CA-mutated disease, and how oral SERD use is changing as combination partners emerge.

Jhaveri is section head of the Endocrine Therapy Research Program, clinical director of the Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What data help you decide whether continuing CDK4/6 inhibition past first-line progression in advanced or metastatic hormone receptor–positive, HER2-negative metastatic breast cancer is the optimal approach for a given patient?

Jhaveri: We have a few datasets now that justify continuing a CDK 4/6 inhibitor beyond progression on first-line therapy. The first dataset we had was from the MAINTAIN trial [NCT02632045], which was a phase 2 trial where patients [had] predominantly [received an] aromatase inhibitor and palbociclib [Ibrance]. Upon progression, they were treated with fulvestrant [Faslodex] and ribociclib [Kisqali]. That showed a statistically significant improvement in progression-free survival [PFS] of 5.29 months [(95% CI, 3.02-8.12) vs 2.76 (95% CI, 2.66-3.25) with switched endocrine therapy plus placebo (HR, 0.57; 95% CI, 0.39-0.85; P = .006)].¹ We were happy to see those data.

That was the first proof of concept, which was further confirmed with the phase 3 postMONARCH trial [NCT05169567] that evaluated a similar question in a larger setting with abemaciclib [Verzenio]. Patients could have received both palbociclib and ribociclib, at approximately 60% and 30% of the patient population, respectively, in the first-line setting.² Upon progression, they were treated with fulvestrant alone vs fulvestrant plus abemaciclib, [with findings] showing statistically significant improvement with the combination, although the delta of difference between the 2 arms was modest. If you look at the Kaplan-Meier curves and the 50% median time point, you see a dip in the curve that reminds us that it's not just the value of PFS that we are looking at. We should also be looking at the hazard ratio, which was supportive of this idea. We have those data to use in clinic. I have been using abemaciclib as a CDK4/6 inhibitor of choice upon progression on a prior CDK4/6 inhibitor, which is predominantly ribociclib in my practice.

For patients with ESR1-mutated disease, could there still be a defined role for single-agent oral SERDs, or are SERD-based combinations becoming the standard?

There is a place for both. We reach for combinations more, given the complexity and the heterogeneity of estrogen receptor–positive disease that we've come to appreciate over the past few years and decades, resistance mechanisms that come with it, and the patient presentation. We take into account what kind of response they had on their prior therapies. Is this really an endocrine-sensitive tumor? What is the site of disease burden? What is the organ involvement? We look at patient comorbidities. We have a conversation with our patients and review the adverse effect [AE] profiles for combination partners as well and have a patient-physician decision-making process.

If you have an [older] patient or a patient who's had a big disease-free interval from early-stage to metastatic disease and then stayed on their first-line therapy for a long time with minimal bone disease progression, I still think a SERD monotherapy could be appropriate. In contrast, if you had a patient with visceral disease burden who did not have a good response to first-line therapy, has multiple organ sites involved, or has other co-occurring mutations, you might feel like you can't trust just 1 endocrine therapy to work as well, and you reach for 2.

Inavolisib has demonstrated strong efficacy in PIK3CA-mutated hormone receptor–positive disease, but its toxicity profile should be considered as well. How do you decide which patients are appropriate for this agent, and how manageable are its associated toxicities in clinical practice?

For inavolisib, I try to select the patients who would have been eligible for the [phase 3 INAVO120] clinical trial [(NCT04191499), including] patients whose tumors have recurred on or within 12 months of their adjuvant endocrine therapy—endocrine-resistant patients, for whom you would have reached for fulvestrant as a backbone. That's a bare minimum that I would stick to in terms of that patient population. The patient then has to have a PIK3CA mutation. Those are the minimum requirements when I'm thinking about such a strategy for a patient in the first-line metastatic setting.

INAVO120 focused on the highest-risk patient population. Patients were only eligible if they had measurable disease, and they were required to have a hemoglobin A1C of less than 6.0% and a fasting glucose level of 126 mg/dL.³ Have I [navigated] around a bit along those lines? If a patient had a fasting glucose level of 140 mg/dL or a hemoglobin A1C of 6.3%, have I used [inavolisib]? Yes, I have. Have I used it sometimes [in patients] without proven measurable disease? Yes, as long as they at least have a PIK3CA mutation and are deemed to have endocrine-resistant disease.

[In INAVO120], despite a hemoglobin A1C cutoff or tight control of the fasting glucose level, we saw grade 3 hypoglycemia. Thankfully, [this level was relatively low] given the strict criteria we followed in the trial. We still see some, which underscores the importance of management.

Luckily, we have strategies. We can support patients with nutrition and lifestyle modifications like low carbohydrate intake when they start these therapies. When they have a prediabetic-range hemoglobin A1C or slightly higher fasting blood glucose levels is when we worry about hyperglycemia being a predominant AE more than in patients who have normal glycemic levels.

We also have data from the phase 2 METALLICA trial [NCT04300790], where we used prophylactic metformin. Patients were ramped up with 2 weeks of metformin even before a PI3K inhibitor was initiated, so that's something that I have also done in these prediabetic patients or those with high fasting glucose levels. We also want to closely monitor the glucose levels for these patients.

Despite these strategies, sometimes we need our endocrinology colleagues on board to help manage the hyperglycemia. Dose reductions are helpful in that context, as well. It is important to be vigilant about this and to be careful about which patients you are offering these therapies to.

References

1. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II Trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer: MAINTAIN trial. J Clin Oncol. 2023;41(suppl 24):4004-4013. doi:10.1200/JCO.22.02392
2. Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib plus fulvestrant in advanced breast cancer after progression on cdk4/6 inhibition: results from the phase III postMONARCH trial. J Clin Oncol. 2024;43(suppl 9):1101-1112. doi:10.1200/JCO-24-02086
3. Turner NC, Im S, Sura C, et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(suppl 17):1584-1596. doi:10.1056/NEJMoa240625