- CDK4/6 inhibitors significantly improve PFS and continue to prevail as the treatment of choice in MBC that becomes resistant to endocrine drugs.
- Scientists continue to study the best time to introduce CDK4/6 inhibitors into a treatment plan, how to sequence them, which inhibitor works best with which AI and whether biomarkers can indicate therapeutic response in patients.
- Although PI3K is altered in 40% of breast cancer and presents a viable therapeutic target, clinical trials have shown only a minor improvement in PFS and major side effects, making the inhibitors perhaps not worthy of approval.
- However, late breaking news indicates that one PI3K inhibitor could potentially pass muster for FDA approval.
This year’s annual meeting of the American Society of Clinical Oncology (ASCO) in June presented several oral abstract sessions and commentary on the treatment of
endocrine-resistant metastatic breast cancer (MBC). Some of the news was good, but a few clinical trials showed only modest results. The endocrine positive breast
cancer subtype accounts for about 70% of all breast cancer.
When a metastatic breast cancer patient is diagnosed with an endocrine-receptor positive/HER2-negative breast cancer subtype, an oncologist often first prescribes an anti-hormonal drug such as an aromatase inhibitor (AI). However, the duration of a response to that class of drugs varies among patients, and after awhile, resistance to the AI starts to develop. But the good news is that overall the addition of a cyclin-dependent kinase (CDK) 4/6 inhibitor to an endocrine drug has made a significant improvement in progression-free survival (PFS) when a patient’s cancer becomes resistant to the AI alone.
Since the advent of the CDK4/6 inhibitor palbociclib (Ibrance) in 2015, patients have now seen two other effective inhibitors with the recent introduction of ribociclib (Kisqali) and amebaciclib (Verzenio). These inhibitors have improved PFS when added to an AI after patients progressed on an AI. For example, in clinical trials, PFS was 14.5–16.0 months in the AI/placebo arms and showed a significant improvement of 25.0–28.1 months in the AI/CDK4/6 inhibitor arms.
Although the CDK4/6 inhibitors have side effects, oncologists can manage the toxicities with dose reductions that do not interfere with efficacy, to maintain a good quality of life (QOL) in many patients.
Some research is now moving toward trying to answer questions to potentially improve PFS and QOL with CDK4/6 inhibitors:
- When is the best time to introduce a CDK4/6 inhibitor into a treatment plan?
- Is there a best way to sequence inhibitors?
- Which inhibitors work best with which AIs?
- Can biomarkers indicate which patients would benefit most from a specific inhibitor?
The not so good news involves the evasive and stubborn phosphoinositide 3-kinase (PI3K), which is altered in 40% of breast cancer that is hormone positive and suspected of promoting resistance to endocrine drugs. However, unfortunately, in trying to target the altered PI3K, researchers are being challenged by little benefit in PFS combined with serious side effects that compromise QOL.
The BELLE-2 and BELLE-3 phase 3 clinical trials, which tested the PI3K inhibitor buparlisib in AI and AI/mammalian target of rapamycin (mTOR) resistance, respectively, showed an overall improvement in PFS of about only two to three months when buparlisib was added to fulvestrant rather than a placebo (BELLE-2: 5.0 vs. 6.9 months; BELLE-3: 1.8 vs. 3.9 months).
The trials took all comers, regardless of whether their PI3K was altered, and patients with a PI3K-activated tumor showed a roughly three-month benefit (4.0 vs. 6.8; 1.4 vs. 4.7, respectively). During the trials, patients experienced significant side effects that entailed frequent dose interruptions, reductions and discontinuations as well as depression and anxiety. Clearly, the results of these two studies showed very little benefit considering the effect of buparlisib on QOL.
The SANDPIPER trial showed similar results with the PIK3 inhibitor taselisib when the inhibitor was added to fulvestrant rather than a placebo, with a PFS of 5.4 versus 7.4 months, for patients with a PI3K mutation. The side effects were similar to buparlisib.
Clinicians are awaiting the results of the phase 3 SOLAR trial, which is looking at combining fulvestrant and the PI3K inhbitor alpelisib versus fulvestrant alone.*
CDK4/6 inhibitors have shown a significant increase in PFS in the presence of endocrine resistance and have manageable toxicities. On the other hand, although PI3K is a viable target in MBC, clinical trials have shown thus far that the PFS benefit is minor and the side effects major, raising the question of whether the drugs tested are worth it.
Notes: *As of late August, Novartis reported that the SOLAR trial has shown positive results in MBC and hopes that the data will result in FDA approval.
Information for this story was taken from several oral abstracts as the ASCO meeting in June 2018: Oral Abstract 1000, Slamon DJ, et al., Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC): Results from MONALESA-3); Oral Absract 1002, Neven, P et al., Abemaciclib for pre/perimenopausal women with HR+, HER2- advanced breast cancer; Abstract LBA1006, Baselga J et al., Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA- mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER; and discussions of the abstracts lead by Angela DeMichele, MD, MSCE of Abramson Cancer Center, University of Pennsylvania and Cynthia X. Ma, MD, PhD of Washington University School of Medicine.