HR-Positive Advances Highlight the Good News in Breast Cancer

Lee S. Schwartzberg, MD, FACP

Recent advancements in the field of breast cancer are reshaping the treatment paradigm for subsets of patients with the disease, bringing new therapies and strategies into focus, according to experts who participated in an OncLive Peer Exchange^® panel.

The panelists said research from key abstracts presented during the 2017 San Antonio Breast Cancer Symposium (SABCS), held December 5-9 in Texas, generated fresh insights into the treatment of pre- and perimenopausal women with hormone receptor (HR)-positive disease, emerging antibody—drug conjugates for HER2-positive and triple-negative breast cancer (TNBC), and the potential for immunotherapy. The experts were particularly enthusiastic about the continuing exploration of CDK4/6 inhibitors, a class of drugs that has emerged since 2015 for women with HR-positive, HER2-negative breast cancer. They also noted the expansion of PARP inhibitors from ovarian to breast cancer. In January 2018, the FDA approved olaparib (Lynparza), a PARP inhibitor, for patients with metastatic HER2-negative disease and a germline BRCA mutation after prior treatment with chemotherapy.

Hormone-Driven Breast Cancer

“I think the science in breast cancer is really making tangible differences in our patients’ lives now and that’s exciting,” said Lee S. Schwartzberg, MD.Three CDK4/6 inhibitors are now approved for patients with metastatic, HR-positive, HER2- negative breast cancer. Palbociclib (Ibrance) was the first agent approved in this drug class in 2015, followed by abemaciclib (Verzenio) and ribociclib (Kisqali) in 2017. These therapies have been targeted for postmenopausal women.

Research at SABCS is likely to expand that population. “We now have another option that is formally clinically tested for premenopausal women—to use ovarian suppression and an aromatase inhibitor [AI],” said Schwartzberg.

According to the phase III MONALEESA-7 trial, adding ribociclib to first-line endocrine therapy (tamoxifen/nonsteroidal AI with goserelin) significantly prolongs progression-free survival (PFS) in both pre- and perimenopausal women with HR-positive, HER2-negative advanced breast cancer.1

That’s significant because “a lot of times, people think you have to take the ovaries out of these patients,” said Hope S. Rugo, MD. “Now we know we don’t have to take the ovaries out.”

Adding ovarian suppression to tamoxifen therapy improves outcomes in premenopausal women with HR-positive, HER2-negative breast cancer; the combination of an AI plus ovarian suppression may be even more beneficial, according to updated data from the TEXT and SOFT trials. “One thing that was really striking to me was that women who were under the age of 35 had this enormous benefit,” Rugo said. “There was more than a 15% difference in disease-free survival (DFS) in patients who got aromatase inhibitor plus ovarian suppression versus tamoxifen, and then an 11.5% benefit in patients who got tamoxifen plus ovarian suppression. What that means is you can give patients either option.”

However, toxicities seem to be more common in patients treated with AIs, and that’s an important factor to consider. “We’re already making women miserable enough with luteinizing hormone— releasing hormone suppression. We make them more miserable with an AI on top of it,” said session moderator Adam M. Brufsky, MD, PhD.

CDK4/6 inhibition plus an AI has also been shown to improve PFS and quality of life in postmenopausal women with HR-positive, HER2-negative advanced breast cancer.2 That’s “very important in the metastatic and palliative setting,” said Komal Jhaveri, MD, noting that available data also suggest significant reductions in pain scores by 8 weeks. The fact that CDK4/6 inhibition doesn’t seem to disrupt quality of life means it may also be a good option for asymptomatic patients with metastases.

HER2-Positive Breast Cancer

“If you give chemo, their quality of life is worse, even though the scans look better,” Francisco J. Esteva, MD, PhD, said. “The fact that quality of life was improved with ribociclib and letrozole was very reassuring.”“Neoadjuvant therapy for HER2-positive breast cancer has been a tremendous success. What we’re trying to do now is refine it,” Brufsky said. What, for instance, is the optimal chemotherapy backbone for use with trastuzumab (Herceptin)/ pertuzumab (Perjeta)? A retrospective stage II to III study of 226 patients³ determined that “the pathologic complete response [pCR] rate was higher in patients treated with THP (taxane/trastuzumab/ pertuzumab), which is interesting because you would think TCHP [taxane/carboplatin/trastuzumab/ pertuzumab] or THP followed by AC [cyclophosphamide/carboplatin] would give you a higher pCR,” Esteva said. “It’s something to keep in mind: Some patients may do very well with THP.”

Also in question: the optimal length of treatment. The SOLD study, a phase III trial, compared 9 weeks of adjuvant trastuzumab versus the standard 12 months, in combination with adjuvant taxaneanthracycline chemotherapy in 2176 patients with early HER2-positive breast cancer. Rugo questioned the choice of a 9-week regimen—“Nine weeks is a funny choice. Couldn’t you give them 12?”—but she applauded the intent behind the research.

“This is a really important question for a number of reasons. One is that the original trials never really asked how long the optimal duration of trastuzumab treatment was. The second is that most people in the world can’t afford trastuzumab,” Rugo said.

The 9-week treatment regimen did not meet the noninferiority criteria. However, the subset of patients who received 100 mg/m2 “seemed to do just as well with 9 weeks versus 12 months,” Rugo said. However, she doesn’t plan on decreasing the duration of treatment for most patients. “Our gold standard is still 12 months,” she said.

Adding trastuzumab to standard adjuvant chemotherapy for tumors expressing low levels of HER2 protein is not advised. The NSABP B-47 phase III trial found that adding trastuzumab did not significantly affect invasive DFS.⁴ “I was actually happy about that result,” Schwartzberg said. “It would have rocked my world if we thought we knew the target and had a test to identify the target and then we didn’t.”

Novel approaches for metastatic HER2- positive disease include trastuzumab deruxtecan (DS-8201), an antibody—drug conjugate that Brufsky nicknamed “TrasD.”

Triple-Negative Breast Cancer

“This one is a topoisomerase 1 inhibitor,” Jhaveri said. A phase I trial presented at the symposium included 2 cohorts: a HER2-positive cohort that was pretreated with either ado-trastuzumab emtansine (T-DM1; Kadcyla) or T-DM1/pertuzumab, and a HER2—low expression cohort.⁵ “In both of these, there was activity seen,” Jhaveri said. Additionally, “there was not increased toxicity, and duration of response was really, really impressive, in some patients as long as 1-and-ahalf years into the study,” she said.Nab-paclitaxel (Abraxane) may lead to increased PFS in women with locally recurrent or metastatic breast cancer.⁶

According to Rugo, who participated in the CALGB 40502/NCCTG N063H trial for patients with TNBC, “when we looked at the subset analysis of estrogen receptor—positive and triple-negative disease, we saw this superiority in the triple-negative group, which is fascinating.”

The phase III GeparSepto trial, which randomized patients to paclitaxel versus nab-paclitaxel followed by AC in both groups, also showed a “much higher” pCR rate in the triple-negative population, Esteva said. “Interestingly, [regardless of] pCR, the event-free survival was significantly better for patients treated with nab-paclitaxel compared with paclitaxel,” he said. So, should clinicians use nab-paclitaxel instead of paclitaxel in triple-negative patients? That’s a “hard call,” Rugo said. “I think that these data as yet aren’t enough to say you should already be using nab-paclitaxel.”

Jhaveri agreed. “Outside of a clinical trial, I’m not sure I am going to personally change my practice. I think we need some kind of validation, at least in the early-stage setting, to be able to justify a 75% grade 1/2 peripheral neuropathy from nab-paclitaxel,” she said.

For women with germline BRCA mutations, there’s a new standard of care: PARP inhibitors—olaparib and talazoparib (BMN-673). The phase III EMBRACA study compared talazoparib, an oral PARP inhibitor, to physician’s choice of therapy; PARP therapy significantly prolonged PFS and was well tolerated.⁷ That finding led Schwartzberg to suggest “germline testing on all metastatic patients.”

“Every triple-negative patient should be tested. The prevalence is high enough, and now you have a new agent,” he said.

Immunotherapy also may be an emerging treatment for triple-negative breast cancer. In the KEYNOTE-086 trial, the objective response rate (ORR) to pembrolizumab monotherapy was 23% in patients with PD-L1—positive, previously untreated metastatic cancer; 3 of the 84 enrolled patients experienced a complete response.⁸

“We’re looking at an explosion of studies now and a lot of excitement,” Rugo said. “Hopefully, we’ll be able to hone it down and figure out who’s going to respond and how we can best capitalize on that.”

Sacituzumab govitecan (IMMU-132), an antibody—drug conjugate, is another promising therapy for TNBC. According to a phase II study presented at the symposium, treatment with sacituzumab elicited an ORR of 34% in patients with heavily pretreated metastatic TNBC.⁹

Hope for the Future

“The target sacituzumab is looking at is a protein called TROP-2, which is a surface glycoprotein that is expressed in more than 90% of triple-negative breast cancers,” Jhaveri said, noting that the drug received FDA breakthrough therapy designation for the treatment of patients who have failed at least 2 prior therapies for metastatic disease.This was an exciting year for various reasons,” Jhaveri said. “We have our first PARP inhibitor for our BRCA-mutant patients. We have exciting new drugs, including the antibody—drug conjugates, and it was nice to see data specifically focused on subgroups include premenopausal patients, where we now have CDK4/6 inhibitor data. It was nice to see a confirmation of our biases in certain areas, including ovarian function suppression, and to have new drugs to offer our patients.”

References

1. Tripathy D, Sohn J, Im SA, et al. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2- negative advanced breast cancer: results from the randomized phase III MONALEESA-7 trial. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS2-05. www.abstracts2view.com/sabcs/view.php?nu=SABCS17L_828&terms=.
2. Singh H, Howie LJ, Bloomquist E, et al. A U.S. Food and Drug Administration pooled analysis of outcomes of older women with hormone-receptor positive metastatic breast cancer treated with a CDK4/6 inhibitor as initial endocrine based therapy. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS5-06. abstracts2view.com/sabcs/view. php?nu=SABCS17L_1028&terms=.
3. Rashmi MK, Akshara RS, Kenneth HR, et al. Patterns of use and effectiveness of neoadjuvant pertuzumab-containing regimens in stage II-III HER2-neu positive breast cancer: A retrospective, single institutional experience. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract P5-20-10. abstracts2view.com/sabcs/view.php?nu=SABCS17L_1398&terms=.
4. Fehrenbacher L, Cecchini RS, Geyer CE, et al. NSABP B-47 (NRG oncology): Phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) à weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk nodenegative invasive breast cancer (IBC) expressing HER2 staining intensity of IHD 1+ or 2+ with negative FISH (HER2-Low IBC). Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS1-02. abstracts2view.com/sabcs/view. php?nu=SABCS17L_989&terms=.
5. Modi S, Tsurutani J, Takahashi S, et al. Safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD3-07. abstracts2view. com/sabcs/view.php?nu=SABCS17L_1094&terms=.
6. Rugo HS, Barry WT, Moreno-Aspitia A, et al. Long-term follow-up of CALGB 40502/NCCTG N063H (Alliance): a randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) +/- bevacizumab as firstline therapy for locally recurrent or metastatic breast cancer (MBC). Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS3-06. abstracts2view.com/sabcs/ view.php?nu=SABCS17L_1333&terms=.
7. Litton J, Rugo HS, Ettl J, et al. EMBRACA: A phase III trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA mutation. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-07. abstracts2view.com/sabcs/ view.php?nu=SABCS17L_1735&terms=.
8. Adams S, Loi S, Toppmeyer DL, et al. KEYNOTE-086 cohort B: pembrolizumab monotherapy for PD-L1-positive, previously untreated, metastatic triple-negative breast cancer (mTNBC). Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD6-10. abstracts2view.com/sabcs/view. php?nu=SABCS17L_1074&terms=.
9. Bardia A, Vahdat LT, Diamond J, et al. Sacituzumab govitecan (IMMU132), an anti-Trop-2-SN-38 antibody-drug conjugate, as ≥3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results. Presented at: 2017 San Antonio Breast Cancer Symposium; San Antonio, Texas, December 5-9, 2017. Presentation GS1-07. abstracts2view.com/sabcs/ view.php?nu=SABCS17L_1727&terms=.