Key Clinical Summary: Optimize post-CDK4/6 sequencing in ER⁺/HER2⁻ mBC based on clinical and molecular resistance patterns

This is a micro-learning module summary of Prof Mark Pegrum’s session which you can find here. Before participating please read our CME and disclosure information which can be found here.

Acknowledgment: This activity is supported by an educational grant from Pfizer Inc. and Arvinas. This online education program has been designed for healthcare professionals globally.

Introduction

This summary explores current strategies for sequencing therapies following progression on CDK4/6 inhibitors in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC). It highlights clinical trial data, molecular resistance mechanisms, and emerging targeted therapies to guide personalized treatment decisions.

CDK4/6 Inhibitor Efficacy: Clinical Trial Versus Real-World Outcomes

The phase 3 MONALEESA-2 trial demonstrated a significant overall survival (OS) benefit with ribociclib plus letrozole versus placebo in the first-line HR+/HER2- mBC setting.

Median OS was 63.9 months for ribociclib plus letrozole vs 51.4 months for placebo plus letrozole (hazard ratio [HR] 0.76, p=0.008).
These results establish ribociclib plus letrozole as a benchmark for first-line therapy in this patient population.

However, real-world data from the Flatiron database, encompassing over 9,000 patients, showed no meaningful OS differences among ribociclib, palbociclib, and abemaciclib. These findings suggest that trial design may influence outcomes more than the specific CDK4/6 inhibitor used.

Mechanisms of Resistance to CDK4/6 Inhibition

Resistance to CDK4/6 inhibitors arises through diverse mechanisms, many of which lack targeted therapies in breast cancers. These mechanisms include:

Hyperactivation of CDK6 via pathways such as Fat/Hippo
Loss of Rb protein
Bypass signaling through cyclin E
P53 gene loss
MDM2 gene amplification
Parallel receptor kinase activation, including FGFR gene amplification

Targeting the PI3K Pathway

Mutations in the PI3K pathway, specifically in the PIK3CA gene, are among the most common molecular alterations in HR+ breast cancer, occurring in ~40% of cases. These mutations are second only to TP53 mutations, which are more prevalent in triple-negative breast cancers.

PIK3CA mutations are particularly enriched in luminal-type tumors
PIK3CA encodes the alpha isoform of the catalytic subunit of PI3K, a key regulator of cell growth and survival. Mutations typically cluster in three functional domains: the kinase, helical and C2 domains.
These mutations are biologically significant, contributing to oncogenic signaling and therapeutic resistance.

Building on this molecular understanding, the INAVO120 phase 3 trial investigated the efficacy of inavolisib, a selective PI3Kα inhibitor, in combination with palbociclib and fulvestrant versus placebo in patients with PIK3CA-mutated, HR+/HER2- advanced breast cancer. Patients had progressed within 12 months of adjuvant endocrine therapy.

The trial met its primary endpoint of progression-free survival (PFS; inavolisib versus placebo, HR 0.42, 95% confidence interval 0.32–0.55) and its key secondary endpoint of OS (0.67 [0.48–0.94], p=0.0190) with statistical significance.
Notably, this marks the first time that OS has been significantly improved by a PI3K pathway-targeted drug in breast cancer.
Hyperglycemia, stomatitis and dry eye/blurred vision were reported at a higher frequency in the inavolisib group, but the discontinuation rate was low.
Time to first subsequent chemotherapy was substantially prolonged with inavolisib by 23 months, highlighting the clinical impact of this regimen in delaying more toxic treatments.

Novel PIK3CA/AKT/mTOR Agents

Beyond inavolisib, the PI3K/AKT/mTOR pathway is a highly active area of drug development. Investigational agents in clinical trials include:

Allosteric inhibitors targeting mutant PIK3CA isoforms (e.g. RLY-2608)
Pan-class I isoform PIK3CA/MTORC1/MTORC2 inhibitors (e.g. gedatolisib)
Mutant-specific PI3K inhibitors (e.g. OKI-129)
Dual PI3K/mTOR inhibitors
Pan-AKT inhibitors (e.g. ipatasertib)
Ipatasertib demonstrated PFS improvement versus placebo in the AKT-altered cohort in the MA.40/FINER trial in HR+/HER2- advanced breast cancer. Although OS data remain immature, the results suggest potential future utility pending longer follow-up.

Another pan-AKT inhibitor, capivasertib, was assessed in the CAPItello-291 phase 3 trial in combination with fulvestrant in aromatase-inhibitor resistant HR+/HER2- mBC.

There was a significant PFS benefit with capivasertib versus placebo in the AKT-altered subgroup (HR 0.5, p<0.001).
Benefit was observed across key subgroups, including those with prior CDK4/6 inhibitor use.

These results suggest capivasertib may offer a meaningful therapeutic option for patients with endocrine-resistant disease, particularly those harboring AKT-pathway alterations.

Conclusion

Endocrine resistance following CDK4/6 inhibitor therapy in HR+/HER2- mBC presents a complex clinical challenge. Resistance mechanisms include Rb loss, CDK6 upregulation, and activation of parallel pathways such as FGFR and PI3K. While many of these alterations remain untargeted, molecular profiling enables identification of actionable mutations. The INAVO120 trial demonstrated that inavolisib, a selective PIK3CA inhibitor, combined with palbociclib and fulvestrant, significantly improves outcomes in this setting. Pan-AKT inhibitors such as capivasertib also show promise in AKT-altered tumors post-CDK4/6 exposure. Continued research into molecular drivers and expanded access to targeted therapies will be essential to optimize post-CDK4/6 sequencing and improve patient outcomes.