ASCO 2018: Updates From the Annual Meeting
Each year, cancer researchers, healthcare providers and patient advocates gather in Chicago for the American Society of Clinical Oncology’s annual meeting. Many of the most important new findings on treatment options, science and patient care are presented at this conference.
LBBC’s copy editor and content coordinator, Eric Fitzsimmons, is at the 2018 meeting, runnning June 1 -5, to provide updates on the most exciting findings. Check back each day for new recaps.
While many of the most anticipated studies will be presented Sunday and Monday, Saturday featured discussions of early phase I and phase II trials that could lead to major changes down the road.
One direction researchers are always exploring is the possibility of new targeted therapies such as phosphatidylinositol-3 kinase (PI3K) inhibitors, the subject of a study shown Saturday. Some breast cancers can send signals through the PI3K pathway that promote tumor growth and the spread of cancer cells to other parts of the body.
This study looked at adding the PI3K inihibitor alpelisib to chemotherapy with nab-paclitaxel. The 48 participants in the phase I/II study had HER2-negative breast cancer that had traveled either in the area near the breast or to other parts of the body, and they had been treated with at least one other line of chemotherapy.
The overall response rate, or the proportion of cancers that had a measurable response to treatment, was 58 percent. That rate was consistent across different subgroups. People with hormone receptor-positive breast cancer had a 60 percent overall response rate, as did people who had been previously treated with taxane-based chemotherapies. The study also showed a clinical benefit rate of 78 percent.
The treatment combination’s side effects were said to be “well tolerated” in the conclusions and by presenter Kari Wisinski, MD, who spoke about the study in the afternoon discussions. Dr. Wisinski noted that this was not a randomized study, but said the results were positive enough to move forward with a large randomized trial.
Another study presented Saturday considered the benefits of giving preventive radiation to the unaffected breast of people diagnosed with early-stage breast cancer who carry an inherited BRCA mutation. This population is at high risk for developing another breast cancer in the healthy remaining breast, which is why many choose to get a preventive mastectomy, surgery to remove the healthy breast to lower that risk. But not all people choose this option. In fact, the authors of the study say most women with BRCA mutations choose not to get the preventive surgery.
The authors said that for this group of women a lumpectomy and radiation to the affected breast protects the treated breast from recurrence as well as it does for peers who do not carry a mutation. But those with a BRCA mutation still have a higher risk of getting another breast cancer in the healthy breast.
This study recruited 162 people who chose between
- standard care of lumpectomy and radiation to the breast where the cancer was found, or
- having those same treatments, plus radiation to the other breast
The participants split evenly, with 81 in each group. At just under 5 years median follow up, nine people in the standard care group were diagnosed with breast cancer in the previously unaffected breast. In the group that got preventive radiation, there were only two cases of a new breast cancer.
Julia White, MD, led the discussion on this study and noted that while it looks like a promising prevention option, there needs to be more research into whether that benefit lasts over a longer period and what methods should be in place to protect other organs from extra radiation.
The RESPECT trial tested if people over 70 with HER2-positive breast cancer could be treated with 1 year of trastuzumab alone instead of the current standard therapy of chemotherapy plus trastuzumab. The study recruited 260 participants between the ages of 70 and 80 and had the stated endpoint of disease-free survival, the length of time a person goes without cancer coming back or dying from any cause.
An interim analysis found that there weren’t enough health-events in the study for the findings to be statistically significant. A new endpoint, called restricted mean survival time, showed the two treatment arms were doing equally well. Still, RESPECT did not meet its goals, and other studies will have to look at this question to change practice.
Though it did not meet its endpoint, the RESPECT trial garnered interest because it touched on two important challenges facing breast cancer research: identifying people who are overtreated, and caring for older people. People over age 70 are underrepresented in many clinical trials and many have breast cancer, meaning there is not good data on how cancers in older people respond to treatments or how older people experience side effects. Shanu Modi, MD, said in the discussion that people over 70 can generally tolerate standard treatment with chemotherapy, and they seem to get the same benefits from the standard treatment as people under 70, but the characteristics and health of each individual has to be considered in every case.
Other studies this weekend will look into de-escalating treatments including the PERSEPHONE trial being presented Monday that will consider if 6 months of trastuzumab can be given for early-stage, HER2-positive breast cancers instead of the current standard of 12 months.
The most talked about breast cancer study on Sunday was the TAILORx trial. This large and long-running trial looked at the treatment of women with early-stage, hormone receptor-positive, HER2-negative breast cancer using the genomic assay OncotypeDX.
OncotypeDX is a test that looks at the genes of hormone receptor-positive, HER2-negative breast cancer tumors. It then gives a Recurrence Score that can help you and your medical team decide on the most appropriate treatment for you. For people with:
- Recurrence Scores below 17, there is usually little or no benefit to getting chemotherapy in addition to hormonal therapy – unless there are clinical features that lead your doctor to recommend it.
- Recurrence Scores over 31, there is a much higher chance of the breast cancer returning after treatment and you would likely benefit from chemotherapy in addition to hormonal therapy.
- For Recurrence Scores between 18 and 30, there has been no clear answer to whether chemotherapy is needed or not.
TAILORx gathered a large sample of 10,273 women who had taken the OncotypeDx test. They were 18 –75 years old and had hormone receptor-positive, HER2-negative breast cancer that had not traveled to the lymph nodes. Those with a Recurrence Score of 10 or lower were assigned to get just hormonal therapy. Those with a score of 26 or above were assigned to get hormonal therapy and chemotherapy.
In the middle were 6,711 women with scores between 11 and 25 that were randomly assigned to get either hormonal therapy alone or hormonal therapy plus chemotherapy. TAILORx aimed to find out if women in this middle group were any less likely to have breast cancer return because they got chemotherapy with hormonal therapy, or if hormonal therapy was sufficient treatment alone. The primary measure for this was invasive disease-free survival, or how long people went without breast cancer returning.
The results showed less than a 1 percent difference between the chemotherapy and no-chemotherapy groups. This means that in people with Recurrence Scores between 11 and 25, getting chemotherapy with hormonal therapy, or getting hormonal therapy alone, worked just as well.
The researchers then looked at the data taking into account each participant’s age, and found that women in this group who were under age 50 saw a benefit from getting chemotherapy with hormonal therapy, and that the benefit grew as the Recurrence Score increased. The researchers don’t know why this trend appeared, but believe it isn’t random and encourage further study into the reasons why.
Lisa Carey, MD, led the discussion on this study and noted that the results in the secondary endpoints were excellent. She emphasized the need to consider clinical factors observed by your doctor in addition to the test scores while making treatment decisions. But the findings in TAILORx are very important. She suggests that, if all other factors agree, women with scores up to 25 should get hormonal therapy alone. For premenopausal women, though, the current recommendation to use hormonal therapy alone up to a score of only 17 should remain.
While TAILORx gives many more women an answer on the need for chemotherapy, Dr. Carey pointed out that there are still questions for some. She said the benefit of giving chemotherapy to postmenopausal women with this diagnosis and scores from 26 to 30 still isn't clear. These women had been in the "intermediate" category before but their treatment was not randomized for study in TAILORx. All women with recurrence scores above 25 were given chemotherapy in this trial.
Dr. Carey also said there were questions treating premenopausal women with scores between 16 and 25. The benefit of adding chemotherapy to this group went up with the recurrence score: Scores above 20 should be more strongly considered for chemotherapy especially as scores get closer to 25. But she said premenopausal women will continue to be of interest as researchers look into why they benefit more from chemotherapy than older women.
CDK 4/6 Inhibitors
CDK 4/6 inhibitors block two proteins, cyclin-dependent kinases 4 and 6, that promote the growth of breast cancer. Last year, two CDK 4/6 inhibitors were granted FDA approval for the treatment of metastatic breast cancer, and the first presentations Sunday morning dealt with studies looking at other uses for these medicines.
The morning opened with the MONALEESA-3 trial looking at the use of the CDK 4/6 inhibitor ribociclib (Kisqali) plus fulvestrant (Faslodex) as the first course of treatment for people with metastatic, hormone receptor-positive breast cancer. Ribociclib has already been shown to help the aromatase inhibitor letrozole (Femara) work better for a similar population.
MONALEESA-3 studied postmenopausal women who had advanced breast cancer that was hormone receptor-positive and HER2-negative. These women had been given no more than one line of hormonal therapy since their breast cancer was diagnosed as advanced. In all, 726 participants were randomized to get either a placebo with fulvestrant or ribociclib with fulvestrant.
The results met the primary endpoint with progression-free survival (the length of time from the start of treatment the cancer does not grow or spread) lasting significantly longer for people who were given ribociclib with fulvestrant. The median progression-free survival for the ribociclib group was 20.5 months compared to 12.8 months in the placebo group.
One concern that was brought up by Angela DeMichele, MD, MSCE, who led the discussion on CDK 4/6 inhibitors, is that these medicines have not shown an improvement in overall survival. She pointed out that while overall survival will be an especially difficult measure to reach, other factors can be used in making decisions, such as the quality of life improvements that come from extending how long a person goes before needing chemotherapy. But this too must be balanced against the side effects of adding a CDK 4/6 inhibitor to a person’s treatment plan.
Results from a phase I/II basket trial of sacituzumab govitecan were presented in December at the San Antonio Breast Cancer Symposium (see Wednesday, December 6), which showed positive results in people who have metastatic, triple-negative breast cancer that grew after trying several other treatments. Sacituzumab govitecan is a combination of a chemotherapy and a targeted therapy, called an antibody-drug conjugate, that targets Trop2, a type of protein that is overexpressed in about 90 percent of breast cancers.
The results presented at ASCO on Sunday were for a different population in that same single-arm, open-label trial: people with hormone receptor-positive, HER2-negative breast cancer. Participants had at least one line of previous treatment for metastatic breast cancer. Everyone in the trial had been treated with at least hormonal therapy, and 98 percent had been treated with chemotherapy.
Of the 54 participants, 31 percent had a partial response and 48 percent had a complete response. The response lasted 7.4 months on average and there were still 7 people taking sacituzumab govitecan at the time of the last assessment. The presentation showed that the median progression-free survival, the amount of time the cancer does not grow, was 6.8 months -- but that figure was not considered final.
Virginia Kaklamani, MD, said that while these results for people with metastatic, hormone receptor-positive breast cancer were generally positive, they were limited by the structure and small size of the trial. Sacituzumab govetican is now being studied further in the phase III ASCENT trial for people with triple-negative breast cancer.
Sunday brought more interest in PI3K inhibition, most notably in SANDPIPER, a phase III study adding the PI3K inhibitor taselisib to fulvestrant for hormone receptor-positive, HER2-negative advanced breast cancer in postmenopausal women. Participants in the trial had cancer that progressed after treatment with an aromatase inhibitor, but had not had more than one line of chemotherapy for metastatic breast cancer.
This study reached its primary endpoint, showing a median progression-free survival of 7.4 months in those taking taselisib and fulvestrant compared to 5.4 months in those taking placebo and fulvestrant. But combining taselisib and fulvestrant caused heavy side effects. About half of participants in the taselisib group had serious side effects, and 16.8 percent stopped taselisib because of side effects.
Cynthia Ma, MD, leader of the discussion of this study, said that while SANDPIPER did technically meet its endpoints, the slight benefits of adding taselisib to fulvestrant did not balance the heavy toll in side effects. She said the findings do not support taselisib being added to clinical practice.
As already seen in the much-discussed TAILORx trial on Sunday, part of making treatment more precise means identifying which people are getting too much treatment and why, and then seeing if they can get less treatment. Monday’s PERSEPHONE trial explored exactly this topic, studying whether trastuzumab (Herceptin) is being given for longer than needed in HER2-positive breast cancer cases.
- the current standard 12 months of trastuzumab or
- only 6 months of trastuzumab
The goal was to see if giving trastuzumab for 6 months would be just as effective at treating the cancer as giving it for 12 months.
The researchers looked at 4-year disease-free survival, the percentage of people living with no signs of disease 4 years after diagnosis, to assess how well each group did with each treatment. They determined that if after 4 years the percentage of people showing no signs of disease in the group given trastuzumab for 6 months was within 3 percentage points of the group getting it for 12 months, the results meant that 6 months of treatment worked as well as 12 months.
At four years, the difference between the groups at was only 0.4 percent, well below the 3 percentage point difference the researchers had set:
- 89.8 percent of people treated with trastuzumab for the full 12 months went 4 years without cancer returning
- 89.4 percent of people treated with trastuzumab for 6 months went 4 years without cancer returning
For people with HER2-positive breast cancer, this means that getting treatment with trastuzumab for 6 months could be just as effective as getting it for a full year, after treatment with chemotherapy.
The researchers also looked at overall survival, the time from the start of treatment to death from any cause, and found that the difference between groups was 1 percentage point:
- 94.8 percent in the 12-month group
- 93.8 percent in the 6-month group
The study also showed how side effects changed when people took trastuzumab for less time. In the 6-month group, 4 percent of people stopped treatment with trastuzumab because of its effects on the heart. In the 12-month group, that number doubled to 8 percent. The hearts of people in the 6-month group who stopped treatment also recovered more quickly than those in the 12-month group.
Some challenges were brought up during the study discussion by Martine Piccart, MD, PhD. Dr. Piccart compared the chosen measurements from this study to other studies on the same topic, including the French PHARE study, which did not reach the same conclusion as PERSEPHONE. She asked whether people would be willing to trade a 2 to 3 percent higher risk of breast cancer returning for 6 months less of trastuzumab. She also brought up factors that limit how easily changing the duration of trastuzumab to 6 months could go into clinical practice, including a number of groups of people that still benefit from a 12-month course of treatment, and new methods of treatment that use trastuzumab in combination with other medicines. (To learn more about these findings, join our upcoming webinar In the Know: HER2-Positive Breast Cancer.)
Ovarian suppression medicines slow or stop the ovaries from making estrogen during breast cancer treatment. They are used in premenopausal women – women who still get their periods – in combination with hormonal therapy, to lower the risk of hormone receptor-positive breast cancer coming back. Chemotherapy also tends to impact how well the ovaries work, which has been suggested as a possible reason why TAILORx showed that women under 50 benefitted from chemotherapy when they had lower OncotypeDX Recurrence Scores (for more on TAILORx, see Sunday’s coverage, above).
Ovarian suppression medicines are now being studied to see if they help tamoxifen, a standard treatment for some people with hormone receptor-positive breast cancer, work better.
The ASTRRA study looked at giving ovarian suppression medicines to women age 45 or younger with early-stage, hormone receptor-positive breast cancer. The women had not yet gone through menopause and had already been treated with surgery and chemotherapy.
The women were first grouped by whether chemotherapy treatment had stopped them from having their periods.
- Women who still had periods after chemotherapy were randomized to get
- tamoxifen alone or
- tamoxifen plus 2 years of ovarian suppression
- Women who stopped having periods during chemotherapy, but who had their periods resume within 2 years of treatment, were randomized to get
- tamoxifen alone
- tamoxifen plus 2 years of ovarian suppression
- Women who stopped having periods completely were not randomized for ovarian suppression
A total of 1,282 women were randomized for treatment with tamoxifen or tamoxifen plus ovarian suppression. The study found that at 5 years after diagnosis
- 91.1 percent of the women who had tamoxifen plus ovarian suppression were living without cancer return
- 87.5 percent of those who had tamoxifen alone were living without cancer return
This way of measuring results is called disease-free survival, or the length of time a person goes without the cancer coming back.
The researchers noted that they were very careful about defining whether a participant was premenopausal (having periods) or postmenopausal (permanently having no periods) after chemotherapy. They suggest that a person whose periods stop during chemotherapy should be monitored for 2 years after completing chemotherapy to see if their periods return before ovarian suppression should be considered for treatment.
But for women under age 45 whose periods do not stop during chemotherapy, adding 2 years of ovarian suppression to tamoxifen significantly improved disease-free survival.