CDK 4 and 6 Inhibitors

The afternoon session on metastatic breast cancers opened with three studies on cyclin-dependent kinase (CDK) 4 and 6 inhibitors. These targeted therapies work by blocking two proteins, CDK 4 and CDK 6, that tell cancer cells to multiply in some tumors. CDK 4/6 inhibitors are usually given alongside a hormonal therapy.

The most notable of today’s studies was the MONARCH 2 trial, a phase III, double-blind trial comparing the combination of CDK 4/6 inhibitor abemaciclib and the hormonal therapy fulvestrant (Faslodex) to fulvestrant with a placebo. All participants had breast cancer that had progressed while they were on hormonal therapy in the past year or got hormonal therapy as a first-line treatment for metastatic breast cancer. But they had not been given chemotherapy as treatment for metastatic breast cancer.

LBBC first reported on abemaciclib in April when Lilly, the company that makes the medicine, announced the results of the MONARCH 2 trial were positive in advance of the full results being presented today.

The primary outcome of the MONARCH 2 trial was progression-free survival, how long the participants lived without the cancer growing. The findings showed people in the abemaciclib group lived an average of around 7 months longer than the people in the placebo group.

• People taking abemaciclib and fulvestrant lived a median of 16.4 months
• People taking a placebo and fulvestrant lived a median of 9.3 months

In the 72 percent of participants with measurable disease, the response rate was 48.1 percent if they were given abemaciclib but 21.3 percent if they got the placebo.

Researchers lowered a participant’s dose of abemaciclib early in the trial when they observed serious side effects, in particular diarrhea. Those who were given the high initial doses continued to have more severe diarrhea than those who started on the lower dose. Presenter George W. Sledge, Jr., MD reported that the lowered dose was strong enough for treatment and that the rate of side effects and the number of people who stopped the treatment because of the effects were much lower at the new level.

There was also a presentation on the TREnd trial, a phase II trial that studied another CDK 4/6 inhibitor, palbociclib. For this study, people with hormone receptor-positive metastatic breast cancer that had progressed while they were taking hormonal therapy were asked to either add palbociclib to that treatment, or stop the hormonal therapy and continue on palbociclib alone.

The primary outcome in this study was the complete benefit rate, which is how many people show a response and have a disease that remains stable for more than 6 months. The group taking both medicines and the group taking palbociclib alone both met the goals of the trial, with 54 percent of people getting both medicines meeting the goal and 60 percent of those on palbociclib alone meeting the goal. But the benefit lasted longer in people receiving both palbociclib and hormonal therapy.

Researchers think the longer benefits show palbociclib may reverse the resistance cancer builds towards hormonal therapy in certain cases.

Ingrid Mayer, MD, MSCI spoke about the studies presented and the way CDK 4/6 inhibitors have changed treatment for hormone receptor-positive metastatic breast cancer. These medicines should be used in first or second-line treatments, in combination with hormonal therapy, she said. But whether to use it in first-line treatment or hold it for second-line treatment will depend on how someone has responded to other medicines and the biology of the cancer, and the same factors will play into the minority of cases where CDK 4/6 inhibitors should not be used.

Neratinib, A Possible Treatment for Brain Metastases

For HER2-positive metastatic breast cancer, the tyrosine kinase inhibitor neratinib showed promise in a phase 2 study as a systemic treatment that works on brain metastases. Researchers say treatments for HER2-positive breast cancer brain metastases are limited, and usually involve a local treatment like radiation therapy.

One cohort in the phase II TBCRC 022 trial followed 39 people with brain metastases given neratinib with capecitabine. Eighteen of the 39 people, or 49 percent, saw a treatment response. Sara Tolaney, MD, MPH, who discussed the HER2-positive studies, said these results showed that a larger study could be possible to explore this combination in treating breast cancers that have traveled to the brain.

PARP Inhibitor Preview

PARP inhibitors are a class of medicine that is being tested to treat breast cancers linked to an inherited mutation in one of the BRCA genes. The ABRAZO trial is a phase II trial that studied treatment with the PARP inhibitor talzoparib in people who in the past had been given a platinum-based chemotherapy, or who had been given at least three treatments without platinum. In total, 49 participants had been treated with platinum-based chemotherapy, and 35 had never had treatment with a platinum.

The response rates were 21 percent for the participants who had been given platinum-based treatments in the past and 37 percent for people who had never been given a platinum-based treatment. This study also found that the longer it had been since a person had been given a platinum-based treatment, the better their response rates. People with a mutation on the BRCA2 gene had somewhat better results than those with a mutation on BRCA1, 24 percent and 34 percent respectively. These results, along with side effects that appeared at the level researchers expected show promise in bringing about further research.

Studies in HER2-Positive Breast Cancer

On Monday, studies of promising treatments for HER2-positive breast cancer surprised some doctors by having weak findings and not showing significant improvement beyond today’s standard treatments.

APHINITY

The new week started with a presentation on the phase III APHINITY trial. APHINITY met its research goals but with such a small improvement in treating the disease that doctors expressed concern about whether adding another medicine to a person’s treatment would be justified.

The aim of APHINITY was to see if adding the targeted therapy pertuzumab (Perjeta) to standard treatment of chemotherapy and trastuzumab (Herceptin) in people with early-stage, HER2-positive breast cancer would prove to be a better treatment. The study met its primary endpoints – which is typically great news for a clinical trial – but adding pertuzumab to standard HER2 treamtent improved outcomes by less than 2 percent in the best cases, and those improvements were mostly seen in a group of people for which standard treatment already has very good results.

The trial randomized 4,805 people into two groups: 2,400 were given pertuzumab, plus standard trastuzumab and chemotherapy, and 2,405 were given standard trastuzumab and chemotherapy plus a placebo.

The study’s primary endpoint was invasive disease free survival. Taking pertuzumab lowered the rate of recurrence and death by 1.6 percent in the total study population:

• Of the people taking pertuzumab, 7.1 percent had a recurrence or died
• Of the people taking the placebo, 8.7 percent had a recurrence or died

The estimated rate of all participants who lived with no return of breast cancer after 3 years increased by only 0.9 percent. 

• 94.1 percent of people taking pertuzumab did not experience a recurrence after 3 years
• 93.2 percent for those taking a placebo did not experience a recurrence after 3 years

The benefit of taking pertuzumab was slightly better for some people with high-risk factors. For example, 92 percent of people with cancer in the lymph nodes and who took pertuzumab lived 3 years without cancer coming back, while only 90.2 percent of those with cancer in the lymph nodes and who took placebo had the same effect. But people who had node-negative cancer there saw no benefit to adding pertuzumab to treatment.

The side effects were similar for both the pertuzumab and placebo groups. But, pertuzumab did result in more cases of serious diarrhea, with 9.9 percent of people taking pertuzumab experiencing that side effect and only 3.7 of their peers on the placebo experiencing it. Less than 1 percent of participants developed heart failure.

The Short-HER Study 

Also in the HER2-positive discussion was the Short-HER study, which explored a different order of treatment for HER2-positive disease that would mean only 9 weeks of taking trastuzumab instead of a full year. The study included 1,253 participants, and while an analysis suggested the shorter schedule was as good as a year of trastuzumab, the trial data was not strong enough to prove that without a doubt. 

Impact on Standard of Care for HER2-Positive Treatment 

APHINITY researchers announced they met their primary endpoint, showing a statistically significant benefit to adding pertuzumab to treatment. But because the improvement in treatment effect was so small, it does not seem that pertuzumab will become part of standard care.

Even before Carey Anders, MD, started discussion of the group of HER2 studies, doctors were expressing surprise at the slight benefit shown in APHINITY. The largest benefit, for people who have node-positive cancer, was only 2 percent. In other participant subgroups, like people who had no disease in their lymph nodes, there was no benefit to adding pertuzumab at all.

Dr. Anders led the discussion of the APHINITY trial, the Short-HER trial and one other, each about either adding to or lessening standard trasuzumab treatment. Though there were just a few more side effects when pertuzumab was added, the improvement in treatment was very small and the cost to the person taking the medicines would be substantial. A person being treated with a year of trastuzumab – at a cost of $56,000 – could expect another $95,000 to add pertuzumab for a  less than 2 percent change in benefit.

Dr. Anders concluded that APHINITY and the other HER2 studies in the session confirmed that chemotherapy with a year of trastuzumab remains the standard of care for HER2-positive, early-stage breast cancer. She did recommend doctors “consider” pertuzumab for node-positive cancers or hormone receptor-negative cancers.

Continued Letrozole

The phase III SOLE trial aimed to see if scheduling time off of hormonal therapy would help people respond to it for longer periods. The study included 4,884 postmenopausal women with hormone receptor-positive, node-positive breast cancer who had taken 4 to 6 years of hormonal therapy.

People were assigned to get 5 more years of hormonal therapy treatment with the aromatase inhibitor letrozole. They were asked to take letrozole regularly for 5 years, or to take it with scheduled breaks for 5 years. In the group that took treatment breaks, treatment was given in four cycles: letrozole taken for 9 months, then not taken for three months. They finished treatment with one full year on letrozole.

The goal of the study was to prove taking hormonal therapy in intermittent cycles could lead to better disease-free survival than taking letrozole continuously. The study did not find that intermittent  treatment improved disease-free survival, but the results were similar to standard, continuous hormonal therapy.

• 85.8 percent of people on the intermittent schedule lived 5 years without a recurrence  
• 87.5 percent of people on continuous treatment lived 5 years without a recurrence

While this won’t change treatment, it may be reassuring for people who have taken a break from treatment for medical or personal reasons to know that breaks don’t impact how well treatment works.

Immunotherapy

Positive results from a phase II trial set up the immunotherapy pembrolizumab (Keytruda) for further study. There were 69 people from the I-SPY2 trial randomized into treatment with pembrolizumab, with 180 placed in the control group.

People who received pembrolizumab had pathological complete response rates triple that of the control in each subgroup. In triple-negative breast cancer, for example, the rate of pathological complete response, which is often defined as no sign of disease found at the time of surgery, was 60 percent for people taking pembrolizumab and only 20 percent for the control group. (These rates were estimated because the way that the trial randomized participants biased the direct results.)  

This will encourage further study of pembrolizumab in larger, phase III trials.