CHICAGO — Physicians managing patients with various breast cancer diagnoses left ASCO 2015 with new data to consider when making decisions every day – some practice-changing, others potentially so.
Key opinion leaders offer their views on positive results from trials investigating an adjunct endocrine therapy, an aromatase inhibitor as an option to tamoxifen, a novel chemotherapy and bisphosphonates.
Results from PALOMA3
Nicholas C. Turner, MD, PhD, a consultant medical oncologist at the Royal Marsden and a team leader at the Institute of Cancer Research in London, and colleagues assessed the safety and efficacy of combining palbociclib (Ibrance, Pfizer), an oral agent that blocks cyclin dependent kinases 4 and 6, with fulvestrant (Faslodex, AstraZeneca) in women with hormone receptor-positive, HER-2–negative advanced breast cancer who had progressed on prior endocrine therapy.
“The palbociclib data with fulvestrant builds on this whole concept of partnering endocrine therapy with another agent,” William J. Gradishar, MD, FACP, professor of medicine in the division of hematology and medical oncology, Northwestern University Feinberg School of Medicine, and breast cancer section editor for HemOnc Today, told Healio.com.
“Palbociclib is approved in combination with letrozole for second-line therapy,” Gradishar said. “PALOMA 3 looked at palbociclib with fulvestrant more as a first-line therapy, and again showed a similar improvement in outcome to the earlier trials.”
The findings not only extend the understanding of palbociclib to the second- and third-line settings but reassure prescribing physicians.
Adam M. Brufsky
“In women who had progressed on an aromatase inhibitor, palbociclib and fulvestrant were compared to fulvestrant alone, and the trial was stopped early because there was a doubling of PFS, which was the primary endpoint, from about 3.8 months to 9 months,” said Adam M. Brufsky, MD, PhD, FACP, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center, University of Pittsburgh, and HemOnc Today editorial board member.
“This gives us more confidence that the original results we saw in the first-line in the phase II trial are correct, and it gives us confidence that the FDA’s decision to give palbociclib accelerated approval was probably the correct one,” Brufsky said.
PFS served as the study’s primary endpoint. Secondary endpoints included OS, response assessment, patient-reported outcomes, safety and tolerability.
Douglas Yee, MD, medical oncologist at the Masonic Cancer Center, University of Minnestota, and editorial board member for HemOnc Today, said many in the community has been eagerly awaiting the presentation and called the results “impressive.”
“It prolonged the PFS, it improved the response rate, and this almost doubles the length of time women could stay on the drug,” Yee said.
The extension of PFS in patients receiving the combination is “remarkable,” Stephen Malamud, MD, associate professor of medicine, hematology and medical oncology at Mount Sinai Hospital, told Healio.com.
“Over 9 months compared to 3 months with a single agent is a push of greater than 100% in PFS, with toxicities no different than what we’ve already known to be associated with the palbociclib — predominately neutropenia without febrile neutropenia and occasional fatigue,” he said.
The findings represents an “enormous gain” for this population of patients who have relapsed or progressed on an aromatase inhibitor, Malamud said.
“This is again part of the cycle that we’ve seen in oncology, luckily enough, which gets us away from standard cytotoxic therapy for a more targeted approach that allows us to address particular aspects of cell division and endocrine resistance without the toxicities of chemotherapy.”
Yee said the “most exciting” lesson learned from the trial was that although targeting the estrogen receptor is good, targeting the estrogen receptor with another molecular inhibitor like palbociclib could be even better.
“It is an advancement in breast cancer showing we can prolong the time of benefit for women with advanced breast cancer who were estrogen-receptor positive by targeting something other than just the estrogen receptor,” Yee said.
Results from NRG Oncology/NSABP B-35
Richard G. Margolese, MD, the Herbert Black Chair in Surgical Oncology and past director of the department of oncology at McGill University’s Jewish General Hospital, and colleagues compared the long-term efficacy of tamoxifen (20 mg daily) or anastrozole (1 mg daily) in postmenopausal women with ER-positive or PR-positive DCIS who underwent a lumpectomy.
“The trial showed anastrozole is effective in that setting, and I’m not sure that was a surprise, but for a long time, people wanted some data to tell them there was a reason they could give an aromatase inhibitor like anastrozole rather than tamoxifen,” Gradishar said.
Both agents target the estrogen growth signal, which hormone receptor-positive breast cancer relies on to grow, but operate in different ways. Tamoxifen blocks ER, preventing estrogen from reaching the cancer cells, whereas anastrozole slows down or stops the manufacturing of estrogen, according to the researchers.
The primary endpoint was breast cancer-free interval, defined as the time from randomization to any breast cancer event including local, regional or distant recurrence or contralateral disease, invasive disease or ductal carcinoma in situ (DCIS). The secondary endpoints were DFS and OS.
William J. Gradishar
“The breast-cancer free interval was slightly improved with anastrozole and, as was expected, there was a somewhat higher risk of fractures but a lower risk of uterine cancer in women who received anastrozole,” Gradishar said.
Although there wasn’t much improvement with anastrozole in women over 60 years old, Brusky said the drug demonstrated good safety all around and expects it will be widely used.
“They’re both generic, so it’s likely going forward that the vast majority of women who are postmenopausal with DCIS and who want prevention of further DCIS will be on anastrozole,” Brufsky said.
The reduction in contralateral breast cancer by almost half was another important finding, according to Yee, and the data provides the many women who have contrary indications to tamoxifen or who don’t tolerate the drug well with a new option.
“I don’t think we’re ever going to do a cancer prevention trial comparing tamoxifen vs. anastrozole,” Yee said. “But this was very provocative data that we might have some additional benefits in reducing the risk of breast cancer with anastrozole.”
Results from BEACON
Edith A. Perez
Edith A. Perez, MD, director of the Mayo Clinic Breast Cancer Translational Genomics program, also an editorial board member for HemOnc Today, presented phase III data from a study comparing the novel chemotherapy drug etirinotecan pegol (NKTR-102; Nektar Therapeutics) with treatment of physician’s choice among patients with late-stage advanced breast cancer.
“The whole idea behind pegylated etirinotecan is that you significantly increase the elimination half-life of the active compound, or SN-38, a metabolite of etirinotecan,” Gradishar explained.
With a 2.1-month improvement in median OS with etirinotecan pegol (12.4 months) compared with treatment of physician’s choice (10.3 months) in the overall study population (HR = 0.87; P = .08), the study did not meet its primary endpoint.
However, Gradisher highlighted the “interesting” finding that a subset of patients with brain metastases had improved survival with etirinotecan pegol compared with physician’s choice (10 months vs. 4.8 months, P < .01).
“Although the overall trial didn’t meet its goal, it’s intriguing to look at this population in particular,” Gradishar said. “It may be worth exploring whether this drug may have some utility.”
Results from study S0307 on bisphosphonates
Results of a SWOG-led study conducted by Julie Gralow, MD, of the University of Washington/Seattle Cancer Care Alliance, Seattle, Wash., and colleagues comparing the efficacy of clodronate, ibandronate and zoledronic acid over 3 years in patients with stage I-III breast cancer already receiving adjuvant systemic therapy were presented in an oral session.
“The use of zoledronic acid has previously been shown to reduce fracture risk in women receiving aromatase inhibitors for early stage breast cancer,” Halle Moore, MD, a medical oncologist in the Taussig Cancer Institute at the Cleveland Clinic, told Healio.com. “In addition, in postmenopausal women, the zoledronic acid also appeared to improve disease-free survival. Based on these findings, a study was conducted to compare zoledronic acid to two different oral bisphosphonate drugs.”
The researchers looked at DFS as the primary endpoint among patients (median age, 53 years; 58% post-menopausal) with various types of breast cancers (77% ER positive, 17% HER2 positive, 16% triple negative, 49% lymph node positive).
“Oral bisphosphonates were similar to the IV bisphosphonate in terms of reduction in bone fracture … and [DFS] was similar between the three arms,” Moore said. “Side effects were somewhat less in the oral bisphosphonate group, with lower incidence of osteonecrosis of the jaw compared with IV bisphosphonate. In addition, the patients appeared to prefer the oral drugs over the IV treatment.”
Moore said the finding have implications for practice in terms of improving patient care and cost.
“This study suggests that we have the opportunity to give an oral drug as a substitute for an IV treatment that perhaps would be a more cost-effective way of treating these bone issues in women with early stage breast cancer,” Moore said.
Gralow J, et al. Abstract 503.
Margolese RG, et al. Abstract LBA500.
Perez EA, et al. Abstract 1001.
Turner NC, et al. Abstract LBA502.
All presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Brufsky, Gradishar, Malamud, Moore and Yee report no relevant financial disclosures.