Latest Developments in Breast Cancer Treatment – Beyond CDK4/6 Inhibitors

Now that their efficacy has been clearly demonstrated and they are in active use in Turkey, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the standard of care for hormone receptor-positive, HER2-negative metastatic breast cancer. The question now is: After disease progression on a CDK4/6 inhibitor and endocrine therapy, what should the next move be?

After CDK4/6

Although CDK4/6 inhibitors have significantly improved survival outcomes for patients with hormone-positive breast cancer, patients always experience disease progression. Acquired resistance is a barrier to treatment. The following options come to mind after CDK4/6 inhibitors; we examine them in turn in this article:

• The PI3K/AKT/mTOR cellular signaling pathway
• Liquid biopsy to identify targetable genetic alterations
• The AKT signaling pathway
• HER2 mutation
• ESR1 mutation
• Histone deacetylase (HDAC) inhibitors and BCL2 inhibitors

Targeting PIK3CA mutations

The SAFIR02 clinical trial found that 28% of patients with hormone receptor-positive, HER2-negative metastatic breast cancer had mutations in PIK3CA, specifically in exons 9 or 20. Mutation was associated with low treatment response and stable disease in these patients; higher rates of disease progression and worse overall survival are therefore observed [for PIK3CA wild-type (nonmutated) disease, a median of 23.5 months versus 19.6 months for those with mutations; P = 0.04]. The data showed that a PIK3CA mutation was prognostic (predictive of the course of the disease).

BOLERO-2 was the first randomized trial to confirm the benefit of targeting the PI3K/AKT/mTOR pathway. It also led to the approval of a PI3K pathway inhibitor specifically targeting mTOR: everolimus. Analysis of tumor tissue or circulating tumor cell DNA (ctDNA) showed that everolimus plus exemestane was effective in both PIK3CA mutant and wild-type tumors, with median progression-free survival of approximately 7 months and 3 months, respectively, compared with placebo. However, it is important to note that these data came from patients who had not previously received a CDK4/6 inhibitor.

Evaluating the benefit of everolimus in patients previously treated with a CDK4/6 inhibitor was one of the aims of the retrospective Italian EVERMET study. Patients received everolimus plus exemestane as either first-line or second-line treatment (with a CDK4/6 inhibitor or another hormonal therapy in the first line).

It is not surprising that patients treated with this regimen in the first line had the best progression-free survival (a median of approximately 12 months), but what is interesting is that progression-free survival was quite similar regardless of whether the patients’ previous treatment was CDK4/6 inhibitor-based or not (medians of approximately 5 and 7 months, respectively). These findings supported the use of everolimus after disease progression on a CDK4/6 inhibitor, but of course these data are retrospective and only hypothesis-generating.

The second PI3K pathway inhibitor to be approved was the alpha-selective inhibitor alpelisib. SOLAR-1, the pivotal study evaluating alpelisib, enrolled patients regardless of mutation status. PIK3CA mutant patients had median progression-free survival of 11 months with alpelisib plus fulvestrant versus 5.7 months with fulvestrant alone (hazard ratio [HR] = 0.56; P = 0.00065); no benefit was shown in patients without the mutation. This finding differed somewhat from the benefit of everolimus seen regardless of PIK3CA mutation status in BOLERO-2.

Although an encouraging trend was shown, overall survival did not improve. Most importantly, patients with visceral metastases benefited more from alpelisib, supporting its use in these high-risk patients.

PIK3CA testing: Should we start with liquid biopsy?

Because performing a tissue biopsy in a patient under follow-up is not practical, the preferred approach is to perform a liquid biopsy first, followed by a tissue biopsy if the result is negative. This recommendation is based on the detection of PIK3CA in ctDNA (circulating tumor DNA) and a SOLAR-1 biomarker analysis that found discordance with tumor tissue. Of 188 patients with wild-type tumors on liquid ctDNA testing, 38% were subsequently found to have a mutation on tumor tissue testing, and these patients benefited from alpelisib. This finding means that if we rely only on ctDNA, we may miss alpelisib treatment in up to 40% of patients.

It was important to assess the efficacy of alpelisib in patients with disease progression after a CDK4/6 inhibitor. Although only 6% of the SOLAR-1 patient population consisted of such patients, the subsequent BYLieve trial included a large proportion of patients with disease progression after a CDK4/6 inhibitor. If the concurrent endocrine therapy was an aromatase inhibitor, patients received alpelisib plus fulvestrant (cohort A); if it was fulvestrant, they received alpelisib plus letrozole (cohort B).

In both groups, the primary endpoint, progression-free survival at 6 months, was met. The percentage of patients alive without progressive disease at 6 months was 50.4% in cohort A and 46.1% in cohort B; median progression-free survival was 7.3 and 5.7 months, respectively. Cohort A met the primary endpoint of more than 50% of patients being alive without disease progression at 6 months.

The findings support the use of alpelisib after treatment with a CDK4/6 inhibitor. It is reassuring to see that the results compare well with SOLAR-1, in which most patients had not previously received a CDK inhibitor (the proportion of patients surviving without disease progression at 6 months was 44%).

More recent studies tried PI3K inhibitors plus CDK4/6 inhibitors plus endocrine therapy in a 3-drug combination, but toxicity has complicated these efforts.

Other targets

Other studies are evaluating the AKT signaling pathway as a target. The randomized phase II FAKTION study compared, in patients resistant to aromatase inhibitors, capivasertib plus fulvestrant with fulvestrant alone. Median progression-free survival was 10.3 months versus 4.8 months (HR = 0.58; P = 0.0044), and median overall survival was 26.0 versus 20.0 months, respectively (HR = 0.59; P = 0.071). The phase III CAPItello-291 trial of this promising combination is currently ongoing.

Other studies, including the phase I/II BEECH trial of capivasertib plus paclitaxel and the phase III IPATunity130 study of ipatasertib plus paclitaxel, show that results are not as good when an AKT inhibitor is combined with paclitaxel rather than an endocrine agent. In both studies, the combinations failed to improve progression-free survival over paclitaxel alone. If we are to target AKT in hormone receptor-positive breast cancer, we should probably use an endocrine partner rather than chemotherapy.

HER2 Mutations

When we think of breast cancer, we think of HER2 receptor overexpression, for which there are highly effective drugs, particularly trastuzumab, pertuzumab and TDM-1. However, HER2 also has alterations other than overexpression, such as amplification and HER2 gene mutations.

The HER2 alterations seen in different cancers are shown below:

HER2 mutations may also prove to be a good target in estrogen receptor-positive breast cancer. One arm of the SUMMIT basket study evaluated, mostly in patients who had previously received fulvestrant and a CDK4/6 inhibitor, neratinib plus trastuzumab and fulvestrant. The response rate was 46% and median progression-free survival was 8.3 months, with remissions of more than 144 weeks in some patients. This study supports the use of a tyrosine kinase inhibitor in patients with a HER2 mutation.

An ongoing phase II study in HER2-mutant tumors is evaluating tucatinib plus trastuzumab (and fulvestrant if hormone receptor-positive) as a second-line or later treatment. If the combination is effective and causes less diarrhea than neratinib, the study will validate the strategy of targeting HER2 mutations with a better-tolerated drug.

The drugs used and being tested in HER2-positive cancers are listed below:

ESR1 Mutations

ESR1 mutations are also among the escape routes cancer cells find during cancer treatment. Unlike PIK3CA mutations, which do not appear to be acquired through treatment, we see ESR1 mutations acquired after CDK inhibitor therapy. According to data from several trials, among patients with hormone receptor-positive, HER2-negative disease progressing on CDK4/6, PI3K or mTOR inhibitors, more than a quarter have ESR1 mutations.

The phase III PRADA-1 study, which included 1,017 patients treated with an aromatase inhibitor plus palbociclib in the first line, showed how these mutations can be acquired and how treatment can clear them when effective. Patients underwent cell-free DNA testing for ESR1 mutations at enrollment and during treatment. At baseline, 3% of patients had an ESR1 mutation, but this affected prognosis: median progression-free survival was 11.0 months for those with mutations and 26.7 months for patients without mutations (HR = 2.3; P < 0.001). Interestingly, for patients whose mutations disappeared early during treatment, median progression-free survival rose to 24.1 months, rivaling their wild-type counterparts. PRADA-1 is evaluating patients who develop an ESR1 mutation but have not yet experienced disease progression, to assess the effect of switching their endocrine agent to fulvestrant.

Other new approaches

Many different drug candidates are being evaluated as oral selective estrogen receptor suppressors. In addition, there are several notable trials, including histone deacetylase (HDAC) inhibitors and BCL2 inhibitors.

Although the HDAC inhibitor entinostat proved disappointing, positive results have recently been reported for tucidinostat. In addition, early results with the BCL2 inhibitor venetoclax, which is effective in some blood cancers, are encouraging. BCL2, which is overexpressed in more than 80% of primary estrogen receptor-positive tumors, is an anti-apoptotic protein.

In a phase Ib study, venetoclax plus tamoxifen led to clinical benefit rates of 62% to 100% in patients previously treated with tamoxifen, CDK4/6 inhibitors or everolimus (plus endocrine therapy). The ongoing phase II VERONICA study will evaluate venetoclax plus fulvestrant after CDK4/6 inhibitor therapy and stratify patients by high and low BCL2 expression.

Sacituzumab govitecan-hziy and other antibody-drug conjugates, as well as combinations involving immunotherapy and fibroblast growth factor inhibitors, are also being evaluated in clinical trials.

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Bonus content: An infographic poster we prepared to help better understand breast cancer treatments