Expanding Breast Cancer Armamentarium Is Increasing the Quality of Individualized Care

Although efficacy and safety data from breast cancer clinical trials investigating agents such as antibody-drug conjugates (ADCs), AKT inhibitors, PI3K inhibitors, and oral selective estrogen receptor degraders (SERDs) can guide treatment decisions and treatment sequencing, these data should be considered along with patient needs and expectations to provide appropriate care, according to Michelina Cairo, MD.

The phase 3 CAPItello-291 trial (NCT04305496) investigated the AKT inhibitor capivasertib plus fulvestrant (Faslodex) vs placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative advanced breast cancer whose disease had relapsed or progressed on or after an aromatase inhibitor (AI), with or without prior CDK4/6 inhibition. The median progression-free survival (PFS) in the overall population was 7.2 months with capivasertib vs 3.6 months with placebo (hazard ratio, 0.60; 95% CI, 0.51-0.71; P < .001).¹

In patients with treatment-naïve, HR-positive, HER2-negative, advanced breast cancer, the phase 3 SONIA trial (NCT03425838) evaluated the efficacy, safety, and cost effectiveness of CDK4/6 inhibitors plus either first- or second-line endocrine therapy, showing no statistically significant or clinically meaningful PFS benefit when CDK4/6 inhibitors were used in the first-line setting. At a median follow-up of 37.7 months, the median time to second progression was 31.0 months in patients who received a nonsteroidal AI (NSAI) plus a CDK4/6 inhibitor followed by fulvestrant upon progression vs 27.8 months in those who received an NSAI followed by fulvestrant plus a CDK4/6 inhibitor upon progression (hazard ratio, 0.89; 95% CI, 0.75-1.04; P = .14).²

“This could spare some patients the toxicity associated with long-term CDK4/6 inhibitor use,” Cairo said of the SONIA findings in an interview with OncLive^®.

In the interview, Cairo, a physician at Sarah Cannon Research Institute at Texas Oncology, The US Oncology Network, in Houston, discussed key insights from trials including SONIA and CAPItello-291; how adverse effects (AEs) inform treatment decisions across the breast cancer spectrum; and where the future is headed for ADCs and oral SERDs in patients with breast cancer.

OncLive: What important data regarding HR-positive, HER2-negative breast cancer management came out of the 2023 ASCO Annual Meeting?

Cairo: ASCO is always exciting, and the 2023 meeting was no exception. I was interested in the SONIA trial. This trial evaluated CDK4/6 inhibitors as first-line treatment vs as second-line treatment after progression on endocrine therapy. This trial found that using CDK4/6 inhibitors in the first line or the second line [did not produce a] statistically significant difference in overall survival [OS]. This came as a surprise for those of us who have become accustomed to using CDK4/6 inhibitors in the first line.

I was also excited about the [phase 3] NATALEE trial [NCT03701334] data, which give us another tool in our armamentarium to help survivors of breast cancer to continue to be long-term survivors. I was impressed by the 25.2% reduction [in the risk of] invasive disease-free survival. Although [this regimen is administered for] 3 years of therapy, I think my patients are ready to gear up.

In addition to the late-breaking therapeutic interventions, I was pleased to see a focus on patient quality of life [QOL]. [Although] endocrine therapy is tolerable and easy compared with chemotherapy, there are still definite effects on patient QOL that should not be discounted. I was excited to see [the presentation by] Kristin E. Rojas, MD, FACS, FACOG, [of Sylvester Comprehensive Cancer Center in Miami, Florida, entitled]: Better Sexual Health for Female Patients on Endocrine Therapy: Strategies Across the Age Spectrum. I was thrilled to see research being done in this area and that [Dr Rojas was] given a position on the national stage to talk about women’s sexual health on endocrine therapy and to share strategies for asking about it, for validating that these are struggles, and for helping treat it. I was excited to see a QOL [presentation] on the podium.

What factors do you consider and prioritize when selecting second-line treatment for patients with HER2-positive disease?

Whenever I think about second-line therapy, I think about 3 factors: the patient factors, the tumor factors, and the efficacy factors. Those are in no particular order except I try to put patients first. [Regarding] the patient factors, [I consider] performance status, disease burden, how quickly [patients] need a response, and the organs that may already be affected by the breast cancer and metastatic disease.

[Regarding] the tumor factors, [I consider] how long the patient was on their first line of therapy. [Did they] progress rapidly within 6 or 12 months? Or have they been on maintenance trastuzumab [Herceptin] plus pertuzumab [Perjeta] from their first line of therapy, [which is the standard-of-care phase 3] CLEOPATRA trial [NCT00567190] regimen? Were they on [this regimen] for years? I also want to [consider patients’] expectations for their second line of therapy. How do I quell their fears?

[Regarding] efficacy, my patients want to know how well [a treatment will] work and how [I know it will work for them]. I always look for a second-line therapy that will answer those 2 questions favorably, that will work well and is expected to work for many patients.

How does the safety profile of fam-trastuzumab deruxtecan-nxki (Enhertu) compare with that of ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive metastatic breast cancer?

[Those are] the top contenders for second-line therapy. T-DM1 was our topline second-line therapy. However, in the trial of trastuzumab deruxtecan vs T-DM1 in the second line, the [phase 3] DESTINY-Breast03 trial [NCT03529110], efficacy was improved with trastuzumab deruxtecan vs T-DM1.

The AE profiles [need to be considered]. When we consider what will be good for patients, what patients will want to take, what they will tolerate, and what will give them the highest QOL, we want to think carefully about the safety profile. Common AEs were gastrointestinal AEs. There was more nausea with trastuzumab deruxtecan than with T-DM1. [In total], 77% [of patients experienced] nausea with trastuzumab deruxtecan vs 30% of patients T-DM1. [However], when using trastuzumab deruxtecan in practice, I found that the nausea is well managed if using a moderately or highly immunogenic regimen. Vomiting is reduced from what we saw in the clinical trial.

Another [AE to note] for patients is alopecia. Trastuzumab deruxtecan [is associated with a] 40% [rate of] alopecia, and less alopecia was seen with T-DM1. I need to counsel patients about the likelihood of grade 1/2 hair loss. For a patient who got used to having their hair again [when receiving] trastuzumab plus pertuzumab, that’s a difficult moment. 

Additionally, neutropenia was a bit higher [with trastuzumab deruxtecan vs with T-DM1], but [the incidence of] grade 3 neutropenia was low, at 16%. With T-DM1, platelets were more likely to be affected and liver function abnormalities were more likely to occur. Those are advantageous for trastuzumab deruxtecan. 

We always need to consider interstitial lung disease [ILD]. Across all the trastuzumab deruxtecan trials, ILD is at an approximately 12% incidence vs an approximately 1.9% incidence with T-DM1. The key for ILD is being knowledgeable about it and aware of it in all lines. Since we first started noticing it more in [patients who received] everolimus [Afinitor] and then more with taxanes, and then finding it with CDK4/6 inhibitors, [clinicians] have a greater degree of comfort with recognizing it on scans and treating it early.

What is the potential future role for T-DM1 in patients with HER2-positive metastatic disease?

In the second-line, metastatic setting, trastuzumab deruxtecan took the place of T-DM1. I still frequently use T-DM1 in the adjuvant setting. For patients who don’t have a complete response to preoperative trastuzumab-based chemotherapy, there is still a great role for T-DM1.

Additionally, Sara M. Tolaney, MD, MPH, [of Dana-Farber Cancer Institute in Boston, Massachusetts], led a small trial, known as ATEMPT [NCT01853748] in carefully selected patients using T-DM1 as adjuvant therapy vs paclitaxel plus trastuzumab. There is a role for [adjuvant T-DM1 in] carefully selected patients who didn’t have neoadjuvant chemotherapy.

What is the potential future role for trastuzumab deruxtecan in HER2-positive breast cancer?

I see it going further forward in the lineup. The [phase 3] DESTINY-Breast09 trial [NCT04784715] is enrolling. [This trial] is studying trastuzumab deruxtecan in the first line vs the traditional CLEOPATRA regimen of chemotherapy plus trastuzumab plus pertuzumab. I see [trastuzumab deruxtecan] moving up [as a] treatment because it’s exciting to give the most patients the best possible drug. [We need to determine whether this is] the best possible drug, but it looks good to me.

What are your thoughts on using the most effective treatment up front instead of saving it for aggressive disease?

There’s a concept that you only have so many pitchers on your baseball team, so maybe you want to save your best pitcher to be your closer. I don’t look at it that way. I only have so many pitchers on my team, but I want my best pitcher to start. I want that pitcher to pitch as many innings as possible. Then, if he tires out, I’ll put in my second-best pitcher and then my third-best pitcher.

[Treating patients with cancer] is not a baseball game where there’s only 9 innings and then pitchers rest. I want there to be as many innings as possible, so I will use my best agents first. The statistics show that with each line of therapy, [some] patients [will] progress quickly, rapidly, and to such a degree that they’re ultimately not eligible for second-line therapy, and fewer of them are eligible for third-line therapy. I want all eligible patients to have access to the best medications at the time that they’re eligible.

What are the biggest unmet needs for patients with HR-positive metastatic breast cancer?

[The biggest unmet need is] overcoming mechanisms of endocrine resistance. As long as we can use it, it’s so gratifying when patients are on endocrine therapy and living a high QOL, the same QOL as their surviving sisters who are on endocrine therapy for 5 to 10 years, and can continue on this medication for years. I want that QOL for all my patients.

However, there are mechanisms of endocrine resistance. ESR1 has been recognized [as one such resistance mechanism] for a long time. Now, we have medications that can target it. Also, we’ve been slicing into [different parts of] the AKT pathway, trying to attack that to get it under control and extend patients’ time on well-tolerated, effective endocrine therapy, especially before moving on to chemotherapy.

How effective is AKT inhibition compared with PI3K inhibition?

The CAPItello-291 trial was presented at the 2023 ASCO Annual Meeting. The PFS data had been presented at an earlier conference. The OS data are still immature. The update at ASCO was primarily focused on the AE profile, because targeting the PI3K pathway, with PI3K at the top, AKT in the middle, and mTOR in third place, has consequences. It’s been a challenge. Many therapeutic interventions are littered on the sidelines because their toxicities were too high.

It was exciting to see the AE update because it clarified [the data presented at the 2022 San Antonio Breast Cancer Symposium]. The AEs seen in more than 10% of patients were rash, diarrhea, and hyperglycemia. No surprises here. There’s an increasing comfort with the diarrhea. Although [the incidence of any-grade diarrhea with capivasertib was] 72.4%, only 9.3% of it was grade 3. [We should] focus on when patients take their anti-diarrheal medications. In the trial, most patients took loperamide, which is expected.

Rash was also a factor. [In total], 38.0% of patients had any grade of rash, and 12.1% of patients had grade 3 rash. In a presentation at ASCO 2023, Hope Rugo, MD, FASCO, [of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center], said her patients were on preventative antihistamines, which is a strategy that’s also come out of our experience with PI3K inhibitors.

We were concerned about hyperglycemia in this pathway, especially with our experience with prior PI3K-targeted agents. [The patients in the capivasertib arm had lower rates of] hyperglycemia than expected. Any-grade [hyperglycemia occurred in] 16.9% [of patients], and grade 3 hyperglycemia occurred in only 2.0% [of patients]. CAPItello-291 allowed [patients who were] diabetic. [Patients] could have a hemoglobin A1C up to 8.0%, and they could have diabetes, as long as they were insulin independent These results are likely to apply to a wide group of individuals, especially in the United States, where we have high rates of hyperglycemia and diabetes, compared with other recent agents targeting PIK3CA mutations that [are associated with] higher rates of hyperglycemia. 

How are CDK4/6 inhibitors sequenced across all lines of HR-positive, HER2-negative disease?

The SONIA trial will make me think about sequencing [CDK4/6 inhibitors] in the first line. In patients who don’t tolerate them well or who aren’t expected to tolerate them well, [I may] start with first-line endocrine therapy. [Based on] the [phase 2] MAINTAIN data [NCT02632045], if I started with a CDK4/6 inhibitor or added it, upon progression, there’s the option to switch CDK4/6 inhibitors and endocrine therapy backbones for greater efficacy.

I still see CDK4/6 inhibitors, for their general tolerability and efficacy, being part of the first line. Maybe we will think of them as first line A or first line B rather than first and second lines. The move now is determining our next-best second-line agent. That area is wide open until more of these data come in.

What data inform the use of oral SERDs in patients with breast cancer?

The oral SERD data have been interesting. I have been excited about this class of medications. The competition, fulvestrant, is an intramuscular injection, 1 injection in each buttock every month. It’s not a pleasant administration method for patients, who would be more interested in an oral medication.

Not all the data are out yet, however, the SERDs are finding their niche in more of the ESR1 mutation category. That is exciting because the data around the development of an ESR1 mutation in metastatic disease, particularly after the first 6 months [of endocrine therapy], and the data regarding ESR1 as a mechanism of primary endocrine resistance in the metastatic setting are emerging. The ability to investigate that area and apply an oral SERD either at the time of progression, or, as some clinical trials are investigating, before clinical progression at the time of molecular movement to [an] ESR1 [mutation], could open an opportunity to keep patients on endocrine therapy longer, delay the development of endocrine resistance, and maintain a less toxic regimen.

However, ESR1 [mutations are] not the only mechanisms of progression. [There may still] be a role for inhibition of the AKT pathway. I’m excited to see the emergence of a well-tolerated AKT inhibitor that can do well in a real-world, largely diabetic patient population, and has manageable AEs. I look forward to the time when we can do studies with combination therapies to see how we can reduce the emergence of dual mutations or do molecular studies early and get the mutations before we see progression on scans.

References

1. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
2. Sonke GS, Van Ommen – Nijhof A, Wortelboer N, et al. Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). J Clin Oncol. 2023;41(suppl 17):LBA1000. doi:10.1200/JCO.2023.41.17_suppl.LBA1000