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Novel combinations with CDK4/6 inhibitors, antibody-drug conjugates, and oral selective estrogen receptor degraders are rapidly changing the treatment paradigm in hormone receptor–positive and HER2-positive breast cancer.
Novel combinations with CDK4/6 inhibitors, antibody-drug conjugates (ADCs), and oral selective estrogen receptor degraders (SERDs) are rapidly changing the treatment paradigm in hormone receptor (HR)–positive and HER2-positive breast cancer, according to faculty from an OncLive® State of the Science Summit™ on breast cancer.
The event, chaired by Eric Winer, MD, professor, medical oncology, director, Yale Cancer Center, physician-in-chief, Smilow Cancer Network, president, American Society of Clinical Oncology (ASCO), focused on where new agents fit into the treatment paradigm for HR-positive disease, how ADCs could benefit patients with metastatic HER2-positive breast cancer, why the use of SERDs in earlier lines of treatment may help prevent disease recurrence, and how multiple drug combinations across clinical studies are paving the way for advances throughout breast cancer treatment.
Winer was joined by his colleagues:
Below, Winer, Krop, Pusztai, Lustberg, and LoRusso summarize the main messages from their presentations.
Krop: Combining a CDK4/6 inhibitor with hormonal therapy is now a standard first-line option for patients with estrogen receptor [ER]–positive breast cancer, given the increase in progression-free survival [PFS] and overall survival [OS] data in some studies. We do not have a head-to-head comparison of these CDK4/6 inhibitors, but given that we have an OS benefit with ribociclib [Kisqali], it provides some rationale for the selection of this agent.
The early data from the phase 2 MAINTAIN trial [NCT02632045] suggests the benefit of CDK4/6 inhibitors after progression on [a CDK4/6 inhibitor]. We need additional data to validate this, but if proven, it does open up a new potential line of therapy for these patients.
The data from the phase 3 PEARL trial [NCT02028507] and the phase 2 Young-PEARL trial [NCT02592746] suggest similar outcomes for endocrine therapy plus CDK4/6 inhibitors compared with chemotherapy, as well as less toxicity. These data further support the use of endocrine therapy prior to chemotherapy in almost all patients without visceral crisis.
In terms of novel therapies [in HR-positive breast cancer], it’s clear that ADCs with novel payloads and bystander effects, which are the second-generation ADCs, have promising activity in HR-positive breast cancer, particularly the HER2-low subset. The data from the [phase 3] DESTINY-Breast04 trial [NCT03734029] showed a significant improvement in efficacy with fam-trastuzumab deruxtecan-nxki [Enhertu] compared with chemotherapy. This study has established HER2-low as a clinically relevant biomarker and, at the same time, trastuzumab deruxtecan as a new standard of care for this patient population.
Sacituzumab govitecan-hziy [Trodelvy] and patritumab deruxtecan also have activity in HR-positive breast cancer. If these eventually become clinically available, it’ll be interesting and complicated [to determine] how to sequence and fit all 3 of these ADCs with overlapping targets and similar payloads into clinical practice. This will take additional clinical trials.
[Regarding] early-stage disease, the phase 3 monarchE trial [NCT03155997] looked at adjuvant abemaciclib [Verzenio] in patients with high-risk, HR-positive, early-stage breast cancer. Patients were randomized to endocrine therapy alone or endocrine therapy plus 2 years of abemaciclib.
The initial analysis of this study showed a significant benefit in terms of invasive disease-free survival with the addition of abemaciclib. Further follow-up has continued to show that, and reassuringly, we saw a larger effect size as time went on. This was important because there was an initial concern that the early benefits may have just been suppression of metastatic progression, rather than elimination of micrometastatic disease, which is our goal in the early disease setting. The fact that we’re seeing better hazard ratios over time supports that this is eventually going to lead to long-term benefit.
These data led to the FDA approval of abemaciclib for the adjuvant treatment of patients with high-risk disease and Ki67 expression over 20%. Ki67 is known to be prognostic but not predictive. The relative benefit wasn’t different between the high- and low-Ki67 [populations]. The reason the FDA required the Ki67 indication was to isolate [abemaciclib] to be used in high-risk patients. Ki67 is also not the easiest biomarker to use in clinical practice. It’s tough to assess across clinics, particularly in the low to moderate range.
Whereas the FDA required Ki67 [of 20%] in this indication [of abemaciclib], ASCO, in a recent guideline update that came out, has instead suggested using abemaciclib in patients according to the original intent-to-treat population of monarchE: either 4 or more positive lymph nodes, regardless of Ki67 expression, or 1 to 3 positive lymph nodes with some other high-risk feature.
Winer: The population of patients with metastatic HER2-positive breast cancer has evolved over time. There are fewer of these patients because adjuvant therapy is so effective. Moreover, those patients who recur after adjuvant therapy have more resistant disease than the patients treated in the past, because they have already received anti-HER2 therapy. Both in trials and in clinical practice, a higher proportion of patients than ever before who have been treated in the metastatic setting for HER2-positive disease have de novo metastatic disease.
The phase 3 DESTINY-Breast03 trial [NCT03529110] compared trastuzumab deruxtecan and ado-trastuzumab emtansine [Kadcyla]. Trastuzumab deruxtecan had a dramatic improvement in PFS compared with T-DM1. Trastuzumab deruxtecan also elicited an improvement in OS that didn’t meet the criteria for an analysis at this point after a limited number of events, but it appears to be impressive based on the hazard ratio. It’s likely that an official significant improvement in OS will be seen soon.
In terms of responses, trastuzumab deruxtecan was associated with a far higher response rate than T-DM1. Almost every patient who received trastuzumab deruxtecan had some amount of tumor shrinkage. The big toxicity with trastuzumab deruxtecan has been pneumonitis. In early studies, there were a number of deaths from pneumonitis, which raised concern. Fortunately, in [DESTINY-Breast03], there were no deaths from pneumonitis. Although there was a higher rate of pneumonitis in the trastuzumab deruxtecan arm than in the T-DM1 arm, it was typically caught early.
Tucatinib [Tukysa] was evaluated in the phase 2 HER2CLIMB trial [NCT02614794], which specifically included and actively looked for patients who had brain metastases. The trial compared tucatinib, trastuzumab [Herceptin], and capecitabine [Xeloda] with placebo, trastuzumab, and capecitabine. There was a significant improvement in PFS and OS [in the investigative arm]. Additionally, [PFS and OS benefits were also observed] in patients with brain metastases. Interestingly, there was an improved outcome in patients who were on tucatinib who recurred in the brain but stayed on their assigned treatment.
It’s still reasonable to start treating patients with HER2-positive, metastatic breast cancer with a taxane, trastuzumab, and pertuzumab [Perjeta], particularly in a patient with de novo disease. That said, if a patient has received trastuzumab and pertuzumab within the past couple of years, you might instead proceed with a second-line therapy, which is now [considered to be] trastuzumab deruxtecan [based on the findings of the DESTINY-Breast03 trial].
For patients with ER-positive, HER2-positive disease, there is still a role for hormonal therapy in combination with trastuzumab and pertuzumab. The phase 2 PERTAIN study [NCT01491737] looked at the addition of pertuzumab to endocrine therapy plus trastuzumab and demonstrated the benefit with this trastuzumab/pertuzumab combination. We should remember to use hormonal therapy in patients who have HR-positive disease, because it can be effective.
Regarding long-term outcomes, in the phase 3 CLEOPATRA trial [NCT00567190], 30% of patients who were on the combination arm [of pertuzumab and trastuzumab plus docetaxel] lived a long time, up to 120 months. Additionally, 16% of patients treated with the combination had still not progressed at 120 months.
This begs the question: Who are these patients? [A long-term follow-up of this study] looked at 99 patients who were long-term responders vs 235 who were not. The long-term responders tended to have non-measurable disease, non-visceral disease, and progesterone receptor–positive disease, which has long been a favorable prognostic factor in many settings.
How should we manage these long-term responders? A pilot study within the Translational Breast Cancer Research Consortium is asking patients if they’re willing to stop their anti-HER2 therapy. These are largely patients who have had an outstanding response to their initial therapy, and this trial is investigating whether some of them could do well in the long term without additional therapy.
The other question that comes up is: Should we be trying harder to potentially eradicate disease and cure patients who present with HER2-positive, metastatic breast cancer, particularly patients who present with de novo disease? We know that a proportion of these patients do well in the long term. In this pilot study, patients are sequenced through a variety of regimens in the hope that perhaps by giving these non–cross-resistant agents, a higher proportion of patients will remain disease-free in the long term.
Pusztai: The phase 3 KEYNOTE-522 trial [NCT03036488] showed that pembrolizumab [Keytruda] shifted the residual cancer burden to lower categories across the entire spectrum of residual disease [in TNBC], and the benefit from pembrolizumab extends to patients who do not achieve pathologic complete responses [pCR]. Using this therapy in the adjuvant setting may substantially contribute to the benefit.
The phase 2 NeoSTAR study [NCT04230109] showed that single-agent sacituzumab govitecan has activity [in TNBC]. In patients [who have] a good response, the pCR rate could be as high as 50%. However, the overall pCR rate is likely much lower than that.
The phase 2 NeoPACT trial [NCT03639948] showed a high pCR comparable with what was seen in KEYNOTE-522 with docetaxel and carboplatin plus pembrolizumab. This treatment does not increase the risk of cardiomyopathy in the long run. Importantly, this study showed that the combination [also provides a benefit] in patients with ER-low disease.
The DESTINY-Breast04 study showed that trastuzumab deruxtecan works in HER2-low, metastatic TNBC and produces similar outcomes as in the much larger population of patients with HER2-low, ER-positive disease.
The phase 3 ASCENT 3 trial [NCT02574455] confirmed what we already suspected: sacituzumab govitecan is a highly effective third-line modality that’s better than any other chemotherapy that it was compared against. [In ASCENT, treatment with sacituzumab govitecan] resulted in a 6-month improvement in median OS.
Lustberg: ER-positive breast cancers comprise most breast cancers that we see, primarily falling in the luminal A and luminal B categories. These categories are classically known as having better prognoses. However, they still comprise most breast cancer deaths that we see.
In ER-positive breast cancer, we face many issues in addition to earlier recurrences, such as late recurrences that can happen many years, up to several decades, after initial diagnosis. We need better therapeutics to deal with this issue.
SERDs are a potential therapeutic strategy. These agents antagonize the ER and help degrade it and can essentially overcome the ESR1-[mutated] receptors, which are revved up and over-active. By focusing on this degradation, the thought is that SERDs can overcome the ESR1 alterations. More than 10 agents are currently in clinical development in the neoadjuvant, adjuvant, and metastatic settings. Early case studies have shown activity in [patients who received prior treatment with] fulvestrant [Faslodex] and have ESR1-mutated disease. SERDs are similar and often oral, though they can have different toxicities.
The phase 3 EMERALD trial [NCT03778931] produced the first phase 3 data for an oral SERD in the second- and third-line settings post-CDK4/6 inhibitors. The PFS advantage was modest at 2.8 months [with elacestrant] vs 1.9 months [with standard of care]. However, the biggest benefit was seen in PFS rates in patients with ESR1 alterations. This trial highlights the need to investigate these agents in earlier lines, perhaps selecting only patients with ESR1 alterations, or combining these SERDs with CDK4/6 inhibitors, mTOR inhibitors, or even other targeted therapies. At the 2022 ASCO Annual Meeting, there was an updated analysis looking primarily at patients who had received no prior chemotherapy. Selecting for the patients who were less pretreated, many of the same trends were seen, with the biggest benefit in those harboring an ESR1 alteration.
The phase 1/2 AMEERA-1 trial [NCT03284957] was 1 of the first reported studies showing that CDK4/6 inhibitors can be safely combined with a SERD, amcenestrant. There was promising activity, and this trial has laid the foundation for a randomized study looking at amcenestrant in combination with palbociclib [Ibrance] as first-line treatment in advanced breast cancer in the phase 3 AMEERA-5 trial [NCT04478266]. Additional updates specifically looked at the population of patients with ESR1 alterations, and this encouraging response rate was seen regardless of ESR1 mutations. There is a part F of the AMEERA-1 trial that is looking at amcenestrant in combination with alpelisib [Piqray]. This highlights the theme that multiple combinations are being looked at for these studies.
I also presented a few highlights from other SERDs in development. Another SERD, giredestrant, is being compared with anastrozole in the neoadjuvant setting, looking at differences in Ki67 [expression]. Many ongoing studies are looking at SERDs in different combinations with CDK4/6 inhibitors.
In terms of future directions for endocrine therapy for patients with breast cancer, we need to establish optimal treatment sequencing following disease progression, particularly after CDK4/6 inhibitors. This continues to be an area of great need. Identifying different predictive markers of treatment sensitivity and resistance is an area of continued development. ESR1 is 1 of these biomarkers, but we need additional ones.
We also need to use specific genomic tools in clinical assessment, [as well as focus on] adherence and toxicity management. Many of these drugs are oral, and we know that patients can struggle with adherence to oral therapies. Additionally, toxicity management is an issue in all stages of breast cancer.
LoRusso: Samuraciclib with fulvestrant is active in patients [with ER-positive, HER2-negative breast cancer] who had previously progressed on CDK4/6 inhibitors. In a phase 1/2 trial [NCT03363893] investigating [samuraciclib plus fulvestrant], patients with TP53 wild-type disease had the best safety outcomes. Samuraciclib is going to be looked at in an upcoming study in combination with oral SERDs, and it has been granted fast-track status by the FDA.
I’m also excited about the future of AZD5305 [in patients with BRCA1/2, PALB2, or RAD51C/D mutations]. It is the first of several [next-generation] PARP1 selective agents. Its safety, pharmacodynamic, and pharmacokinetic profiles [all show potential in findings from the phase 1/2a PETRA trial (NCT04644068)]. We did see resistance though; many of the patients who responded went on to progress. That may have had to do with prior platinum exposure or prior PARP inhibitor exposure, as platinum resistance lends itself to PARP inhibitor resistance. We need to see whether bringing this drug up earlier in the therapeutic regimen will have a longer-lasting, more durable, sustainable impact. The future [looks exciting] for this series of [PARP1 selective inhibitors].