Sequential Adjuvant Therapy in Advanced Breast Cancer
Presentation by Dr Ruth O'Regan, University of Rochester Medical Center
At the 2024 University of Kansas Breast Cancer Year in Review presented by Total Health, Dr Ruth O’Regan from The University of Rochester Medical Center presented updates on the use of sequential adjuvant therapies and targeted treatments for patients with advanced stage hormone receptor positive (HR+) breast cancers.
Introduction
Dr O’Regan began with a brief overview of trials examining the use of first line (1L) cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), specifically palbociclib, abemaciclib and ribociclib, in combination with endocrine therapy (ET) for patients with advanced breast cancer whose tumors are HR+ and human epidermal growth factor receptor negative (HER2-). Results from these trials showed essentially a doubling in progression-free survival (PFS) with a CDK4/6i in combination with ET, as compared to ET alone, although surprisingly trials with palbociclib (with some caveats) failed to show a benefit in overall survival (OS), which suggests there may be some nuances in the overall benefit of one CDK4/6i versus another in the 1L setting.
Dr O’Regan noted the open question of whether all patients need a CDK4/6i in the 1L setting. In the SONIA trial, there was significant improvement in PFS with CDK4/6i in combination with aromatase inhibitor (AI) versus AI alone as a first line treatment (median PFS, 24.7 mo vs. 16.1 mo; hazard ratio [HR] =0.59; P<0.0001), however, for the primary endpoint, PFS2 (meaning PFS in the second line setting), there was no significant difference when using a CDK4/6i in the first line versus the second line (2L) setting (31.0 mo vs. 26.8 mo; HR=0.87; P=0.1), suggesting that not all patients may need the added toxicity, both in terms of adverse events as well as treatments costs, associated with using ET in combination with a CDK4/6i. Despite this, however, she noted data from the MONALEESA 2 trial showing an OS benefit of ribociclib when added to ET versus ET alone (63.9 mo vs. 51.4 mo; HR=0.76; P=0.004), and owing to this data, in the 1L setting, most clinicians would be inclined to use a CDK4/6i with ET.
Tumor Genomic Considerations
Dr O’Regan noted that, in advanced breast cancers, it is important to distinguish between genomic alterations that occur at the time of diagnosis (e.g., TP53 and PIK3CA) versus those that are acquired, meaning occurring at the time of disease progression (e.g., ERBB2, AKT1, as well as mutations in the estrogen receptor gene, ESR1). She further noted some guidance on when and how to test for mutations (BOX 1). In particular, Dr O’Regan noted that mutations in downstream signaling pathways, like the PIK3CA pathway, are important to consider as they could be important mediators of endocrine therapy resistance, and targeted treatments could be available. For example, Dr O’Regan noted the INAVO120 study, in which patients who had PIK3CA-mutant, HR+/HER2- advanced breast cancer, and progression during or within 12 months of completing ET, were treated with inavolisib, a PI3 kinase inhibitor drug, or placebo in addition to CDK4/6i + ET. Results from INAVO120 showed a significant benefit of inavolisib over placebo, with a median PFS of 15.0 versus 7.3 months (HR=0.43; P<0.0001), and OS results, while they will require a longer follow up, also appear to favor the inavolisib arm. Dr O’Regan also noted the particularly poor outcome in the placebo arm, which could suggest these patients (due to their PIK3CA-mutant status) likely have ET-resistant disease.
| Box 1. Tumor Genomic Profiling: When and How Should We Check? |
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· Check tumor DNA on the metastatic tissue sample, or using circulating tumor DNA (ctDNA) · Genomics should be retested using ctDNA upon disease progression, to check for acquired mutations (e.g., ESR1, ERBB2, or AKT1) · If necessary, primary tissue should also be tested for non-acquired alterations (e.g. PI3-kinase mutations) · Based on presence or absence of genomic alterations (e.g., ESR1 mutation), an optimal combination agent for ET can be chosen |
Post-Progression Trials
In the second portion of her presentation, Dr O’Regan reviewed the current options for patients in the second line (2L) setting who are candidates for combination ET, which depends largely on the genomic characteristics of their tumor. Specifically, for those without a relevant molecular alteration who are not candidates for any targeted therapy, options include a switch in their CDK4/6i agent, or another type of therapy called an mTOR inhibitor. For those who do have what is known as an actionable genomic alteration in their tumor, options include ET in combination with a PI3-kinase or an AKT inhibitor, an oral selective estrogen receptor modulator (SERD) for those with ESR1 mutations, or a tyrosine kinase inhibitor (e.g., neratinib) for those with ERBB2 mutations. Additional options include standard chemotherapy, or increasingly, antibody-drug conjugates (ADCs) which combine an antibody targeting a cancer-specific cell surface molecule with a cytotoxic drug molecule that enters and kills the cancer cell.
Dr O’Regan then reviewed results from several “post-progression” trials, which generally examined outcomes in HR+/HER2- patients who had previously been treated with ET and a CDK4/6i, and then their disease progressed. In the MAINTAIN trial, most patients (85%) had received CDK4/6i therapy with palbociclib in the 1L setting (which had been the standard of care therapy at the time), and patients were randomized to either ribociclib with a switch in ET, or to placebo with a switch in ET. The results showed a significant improvement in median PFS with ribociclib versus placebo (5.29 vs. 2.76 mo; P=0.006).
Similarly, in the PACE trial, most patients (85-95%) had received 1L palbociclib, and were randomized to a SERD (fulvestrant), either alone, or in combination with palbociclib or avelumab, an immunotherapy type drug. Results from PACE showed no significant difference in PFS between the fulvestrant versus the fulvestrant + palbociclib arms (4.8 vs. 4.6 mo), however, there was a significant benefit in PFS for patients in the combination therapy arm with avelumab immunotherapy (8.1 mo), and Dr O’Regan noted previous experimental evidence that CDK4/6i can actually increase the immunogenicity of cancers, and therefore increase their susceptibility to killing by the immune system.
In the PALMIRA trial, all patients had received previous treatment with palbociclib + ET and were randomized to fulvestrant or an AI (letrozole), depending on what they had received in the 1L setting, either alone or with palbociclib. Notably, the results of this trial were negative, in that patients randomized to ET + palbociclib had similar 12-month PFS relative to those on ET alone (12.4% vs. 12.3%), and Dr O’Regan suggested that in such patients, while switching the CDK4/6i can be considered, continuing the same CDK4/6i (in this case, palbociclib) was not beneficial. This is an important consideration, because nowadays many patients may have received a CDK4/6i in the adjuvant (post-surgery) setting. In this regard, Dr O’Regan reviewed study design for the postMonarch trial, in which patients with metastatic HR+/HER2- disease who had prior therapy with a CDK4/6i plus an AI, or adjuvant treatment with a CDK4/6i + ET will be randomized to either CDK4/6i (abemaciclib) or placebo, in combination with a SERD (fulvestrant), with results to be reported this year.
Growth Factor Pathways and ET Resistance
One of the ways that breast cancer cells develop resistance to ET is through increased activation of other growth-promoting pathways, and Dr Regan noted that by blocking the later steps in these pathways, resistance to ET can be overcome. One such target is the mammalian target-of-rapamycin, or mTOR, and when clinicians are thinking about strategies to overcome ET resistance, she noted “Don’t forget about everolimus”, a drug which targets mTOR, and is fairly well tolerated. For example, in the TAMRAD trial, patients with metastatic, ET-resistant breast cancer received either ET with tamoxifen alone, or tamoxifen in combination with everolimus. The results showed a near doubling in the time to progression (TTP) with everolimus versus tamoxifen alone (8.6 mo vs. 4.5 mo; P=0.0026). Similarly, in the BOLERO-2 trial, patients received ET with an AI (exemestane), either alone or with everolimus, and there was again a highly statistically significant benefit of using everolimus with exemestane versus exemestane alone (10.6 mo vs. 4.1 mo; P = 3.3 x 10-15).
Dr O’Regan noted that another mechanism of ET resistance is overactivation of the phosphatidyl inositol 3 kinase (PI3K) pathway, by virtue of PI3K gene mutations. In the SOLAR-1 trial, patients with or without PIK3CA mutations were randomized to treatment with the PIK3CA inhibitor alpelisib or placebo in combination with fulvestrant. The results showed a significant benefit of alpelisib for patients with PIK3CA mutations, with a median PFS of 11.0 months versus 5.7 months in the respective groups (P<0.001). Dr O’Regan noted, however, that only a small proportion of patients in SOLAR-1 had received a prior CDK4/6i, and this led to the design of the BYLieve trial, which evaluated the efficacy of alpelisib + fulvestrant in patients who had prior therapy with a CDK4/6i and an AI. The primary endpoint in the trial was the proportion of patients alive without progression at 6 months, and she noted the study met its primary endpoint, with 50.4% of patients alive and without progression at 6 months, and a median overall PFS of 7.3 months.
Dr O’Regan also reviewed results for another targeted therapy, capivasertib, which inhibits signaling through the AKT pathway, which can also be overactivated in patients with PIK3CA mutations. In the CAPItello-291 trial, patients received treatment with either capivasertib + fulvestrant or placebo + fulvestrant, and most patients in the trial had a PIK3CA mutation. The results showed a significant benefit for the capivasertib combination versus the placebo combination in the overall population, with a PFS of 7.2 versus 3.6 months (P<0.001), with similar results seen for patients who had mutations in the AKT pathway 7.3 versus 3.1 months (P<0.001). While the study was not powered to detect differences in OS, results thus far appear to favor capivasertib, and Dr O’Regan noted that some adverse events like hyperglycemia may be less frequent with capivasertib versus alpelisib.
Oral SERDs
In the final portion of her presentation, Dr O’Regan briefly highlighted some of the recent results with the oral SERDs, including those of the EMERALD trial, which evaluated the use of the recently approved agent elacestrant, as compared with the current standard of care (SOC, either fulvestrant or an AI), in fairly heavily pre-treated patients with metastatic, HR+/HER2- breast cancer, all of whom had received a prior CDK4/6i and up to 1 line of chemotherapy for their disease. She noted the results from EMERALD (BOX 2) which show a fairly modest improvement in progression or death in the overall population (30% improvement), in contrast to the benefit in PFS seen in the population of patients with ESR1 mutations (45% improvement). These findings led to the recent approval of elacestrant for patients with advanced, endocrine-resistant breast cancer having ESR1 mutations.
| Population | Elacestrant | SOC | P Value |
|---|---|---|---|
| All Patients | 2.79 mo | 1.91 mo | 0.0018 |
| ESR1 Mutation | 3.78 mo | 1.87 mo | 0.0005 |
Additional results have further shown that the longer patients have been without progression on a prior CDK4/6i in the first line setting (an overall indicator of overall endocrine sensitivity), the better the observed PFS while on elacestrant (BOX 3). Dr O’Regan noted that the latter results might argue for an earlier use of elacestrant as well as other oral SERDs, before breast cancers have progressed to a more endocrine resistant state.
| At Least 6 Months | At Least 12 Months | At Least 18 Months | |
|---|---|---|---|
| Median PFS, Elacestrant | 4.14 mo | 8.61 mo | 8.61 mo |
| Median PFS, SOC | 1.87 mo | 1.91 mo | 2.10 mo |
Summary
Summarizing, Dr O’Regan noted that, while standard 1L therapy for patients with advanced HR+/HER2- breast cancer remains ET in combination with a CDK4/6i, while newer agents such as inavolisib await possible approval. Following progression, she suggested that therapeutic decisions should be guided by genomic analysis of the tumor biopsy specimen, or with the use of circulating tumor DNA (ctDNA) testing (BOX1). For patients with tumor mutations in PIK3CA, alpelisib or capivasertib can be considered, while for patients with ESR1 tumor mutations, oral SERDs such as elacestrant are an option. For patients whose tumors have no actionable genomic alterations, a switch in their CDK4/6i, or mTOR inhibition with everolimus, in combination with ET, can be considered. Other options in this setting continue to include chemotherapy, or one of the more recently approved ADCs. Lastly, she noted that strategies for sequencing of all these agents continue to evolve, and will require further study.
Speaker Disclosure Information: Dr O’Regan reported serving as an advisor for Pfizer.
You can see the full presentation from the 2024 University of Kansas Breast Cancer Year in Review here:
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