FUTURE DIRECTIONS

CDK 4/6i (palbociclib, ribocilib or abemaciclib) in combination with either AI or fulvestrant is the standard first-line treatment for HR+/HER2 negative MBC.^2–5 Greater understanding of the PI3K/AKT/mTOR pathway has led to the development of therapies that specifically target this pathway. Table 1 highlights clinical trials currently underway evaluating additional therapeutic strategies to target this pathway.

In the SOLAR-1 study, only 5–6% of patients across all groups received previous treatment with a CDK 4/6i.²¹ Alpelisib has been approved in combination with fulvestrant in patient patients who have progressed on endocrine therapy.¹⁹ This raises the question about the role of alpelisib in patients who have progressed on CDK 4/6i. Clinical trials are currently ongoing to answer this question. Initial results from the BYLieve study were recently reported.²⁶ This phase II open-label non-comparative study is evaluating the role of alpelisib in the treatment of HR+/HER2 negative PIK3CA mutated MBC. Initial results reported the cohort of patients with immediate prior treatment of CDK 4/6i + AI and went on to receive alpelisib + fulvestrant. At 6 months, the proportion of patients without disease progression was 50.4% (95% CI, 41.2–59.6).²⁶ Additional cohorts are waiting to be reported, this includes patients with immediate prior treatment with CDK 4/6i+fulvestrant, systemic chemotherapy or endocrine therapy.

Alpelisib has also been studied in HER2 positive breast cancer. HER2 amplification and PIK3CA mutation can often both be seen simultaneously in breast cancer. This co-occurrence has been shown to have decreased response to HER2 directed therapies.²⁷ Hanker and colleagues developed a mouse model of HER2+ and PIK3CA mutated breast cancers. It was found that dual HER2 amplification and PI3KCA mutation resulted in faster time to disease progression and conferred resistance to herceptin alone and in combination with pertuzumab and lapatinib. Interestingly, resistance was overcome with treatment with PI3K inhibitor.²⁷ In a Phase I study by Jain and colleagues, patients with HER+ MBC who had progressed on taxane and trastuzumab therapy were treated with alpelisib in combination with T-DM1.²⁸ Seventeen patients were enrolled and median number of prior therapies was three. In the fourteen patients that were evaluable for response, the overall response rate was 43%. The most frequent toxicities included fatigue, rash, thrombocytopenia and anemia, hyperglycemia, elevated liver enzymes and gastrointestinal toxicities.²⁸ These studies show promising results with alpelisib in the treatment of HER2 positive breast cancer but further studies will need to be conducted to confirm these findings.

CONCLUSION

The PI3K/mTOR pathway plays an important role in cell growth, proliferation and survival. Preclinical and clinical studies have demonstrated that inhibiting this pathway can be a key therapeutic strategy in the treatment of HR+/HER2 negative MBC. Alpelisib is the first PI3Ki approved for the treatment of HR+/HER2 negative MBC in patients who have a PIK3CA mutation and who have received prior endocrine therapy¹⁹ Further studies will need to be performed to evaluate the role of alpelisib in patients previously treated with CDK 4/6i and the role in other subtypes of breast cancer including HER2 positive disease. The development of alpelisib adds to the non-chemotherapy options for patients with HR+/HER2 negative MBC and is yet another demonstration of the shift in cancer care towards personalized medicine and targeted therapeutics.

Disclosure

Alpelisib in the Treatment of Breast Cancer: A Short Review on the Emerging Clinical Data

FUTURE DIRECTIONS

CONCLUSION

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