Tripathy Reviews Pivotal Breast Cancer Presentations

Debu Tripathy, MD

A number of crucial findings were presented over the course of 2015 that helped to characterize an ever-growing trend toward personalized medicine in the treatment of breast cancer, according to Debu Tripathy, MD, who presented a talk focused on highlights from the 2015 ASCO Annual Meeting and the 2015 San Antonio Breast Cancer Symposium (SABCS).

To fully capture the top research, Tripathy compiled a list of 10 key studies that were presented at the two meetings. These intriguing clinical trials provide new insight into existing therapies while fueling immunotherapy excitement, noted Tripathy chair, Breast Medical Oncology, The University of Texas MD Anderson Cancer Center.

Optimizing DCIS Treatments

“While there are some challenges with personalized medicine, our knowledge in that area is growing,” said Tripathy. “Becoming a state-of-the-art breast medical oncologist really takes a lot of knowledge and understanding of these trials and that’s what our hope is to do is to present data that are coming out of the research world and translating them into how we actually take care of patients.”A number of intriguing clinical trials focused on the treatment of patients with hormone receptor (HR)-positive breast cancer, including those with ductal carcinoma in situ (DCIS). Chief among these studies were updates from the phase III IBIS-II study and the NSABP B-35 trial, which compared tamoxifen and anastrozole for postmenopausal women with DCIS.

In the IBIS-II study (Cuzick J, et al. SABCS; abstr S6-03), breast cancer recurrences were similar between the two hormonal therapies, although there was a significantly higher rate of secondary cancers in the tamoxifen arm. Overall, there were 17 gynecologic cancers in patients who received tamoxifen versus one in the anastrozole arm. Additionally, thromboembolic events were more common with tamoxifen versus anastrozole (24 vs 7, respectively; P = .003).

The rate of nonmelanoma skin cancers was lower in those receiving anastrozole (odds ratio [OR], 0.43; P = .04). However, more patients in the anastrozole arm experienced fractures compared with tamoxifen (OR, 1.36; P = .03).

In the NSABP B-35 trial (Ganz PA, et al. SABCS; abstr S6-04), a significant 27% reduction was seen in recurrence with anastrozole compared with tamoxifen (P = .03). Moreover, a difference was not observed in overall quality of life between women in the tamoxifen and anastrozole groups for physical or mental component scores using the SF-12 tool (P = .02 and P = .38, respectively).

Adding Denosumab Improves DFS

“Treating DCIS with anastrozole versus tamoxifen is something that can be applied in the clinic right now,” said Tripathy. “Anastrozole is a better drug and has a lower rate of contralateral recurrence and has a better side effect profile in some cases.”A follow-up analysis found that adding denosumab to an aromatase inhibitor (AI) helped to prevent fractures while reducing the risk of recurrence and death in postmenopausal women with HR-positive breast cancer (Gnant M, et al. SABCS; abstr S2-02). The addition of low-dose denosumab to an AI reduced the number of clinical fractures by half, with 176 fractures reported in patients receiving placebo, and only 92 fractures observed in the denosumab arm (HR, 0.50, P <.0001).

“Denosumab has really been shown to lower the fracture rate, and there is a borderline improvement in recurrence risk,” said Tripathy. “How we use bone-targeted agents in early phase disease–whether it is just for bone density and fracture or whether it actually has an adjuvant effect in lowering the risk of recurrence–is of interest.”

In the longer follow-up, women treated with denosumab plus standard AI therapy experienced a 19% relative improvement in disease-free survival (DFS). The absolute benefit was about 1% after 3 years, 2% after 5 years, and 3% after 7 years of follow up. Additionally, benefits may be greater for those who start treatment earlier (HR, 0.61) and for those with larger tumors (HR, 0.66).

CDK 4/6 Inhibition With Fulvestrant

“We need longer follow-up from these studies, but the implication is that these bone protecting agents not only protect you from things like osteoporotic fractures but may even protect the bone itself from developing metastases and other areas of metastasis as well,” Tripathy observed. “Patients who have even a minimal increase in the risk of fracture, based on bone density and other indices, might now reasonably be treated with such agents.”Findings from the phase III PALOMA-3 study were presented at ASCO, showing a doubling in progression-free survival (PFS) with the addition of palbociclib (Ibrance) to fulvestrant (Faslodex) for patients with pretreated HR-positive, HER2-negative breast cancer (Cristofanilli M, et al. SABCS; abstr P4-13-01). Median PFS was 9.5 months with the palbociclib combination versus 4.6 months in the placebo arm (HR, 0.461; 95% CI, 0.360-0.591; P <.0001).

Based on these findings, the FDA approved a supplemental new drug application for palbociclib to be used in combination with fulvestrant on February 19, 2016. The FDA initially granted palbociclib an accelerated approval in February 2015 as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer.

The initial approval for palbociclib was based on findings from the phase II PALOMA-1 trial (N Engl J Med. 2015;373(3):209-219). In this open-label phase II study, the median PFS with palbociclib was 20.2 versus 10.2 months for letrozole alone (HR, 0.488; P = .0004).

“No difference in survival is yet apparent,” explained Tripathy. “A big questions remains regarding the biology and optimal clinical management after progression on palbociclib.”

HER2-Targeted Therapy Advancements

The confirmatory phase III trial for palbociclib’s accelerated frontline approval is PALOMA-2. This study is comparing the combination of palbociclib and letrozole with letrozole alone as a frontline treatment for postmenopausal women with ER-positive, HER2-negative advanced breast cancer (NCT01740427).A 3-year exploratory analysis of the phase III ExteNET trial presented at SABCS (Chan A, et al. SABCS; abstr S5-02) showed an invasive DFS rate of 92% with neratinib versus 89.9% for placebo in patients with breast cancer who were treated with one year of adjuvant trastuzumab following surgery (HR, 0.74; 95% CI, 0.56-0.96; P = .023). In those specifically with HR-positive disease, the 3-year DFS rate was 94.4% versus 88%, for neratinib and placebo, respectively (HR, 0.43; 95% CI, 0.26-0.70; P <.001).

However, 95.4% of patients treated with neratinib experienced all-grade diarrhea (39.9% was grade 3). The median duration of grade 3 diarrhea was 5 days and 1.4% of patients required hospitalization. Quality of life scores by FACT-B were distinctly worse during the first 30 days in the neratinib arm, related to diarrhea; however, after 30 days, the two groups reported similar scores.

In an early report from a phase II study released during a conference call by Puma Biotechnology, the developer of the drug, just 16% of patients experienced grade 3 diarrhea with prophylactic loperamide. The open-label study was initiated to address the high-level of neratinib-associated diarrhea in the ExteNET trial, in which patients did not receive prophylactic loperamide. Full results from the study are anticipated later this year, along with a regulatory filing for neratinib.

New Cardiac Safety Approach Effective in MANTICORE

“The grade 3 toxicity rate of diarrhea was quite high. It was an issue,” Tripathy noted. “There is a trial going on right now using preventive loperamide, and the hope is to get this toxicity down to a more manageable 10% range. We'll see if that can do it.”In the 3-arm MANTICORE study (Pituskin E, et al. SABCS; abstr S1-05), prophylactic administration of standard heart failure medications helped preserve left ventricular ejection fraction (LVEF) in patients treated with trastuzumab for HER2-positive metastatic breast cancer. These findings represent the first-ever demonstration of a successful approach for curbing trastuzumab-related cardiac toxicity, suggested Tripathy.

In the three-arm study there was a 3% and a 1% decrease in LVEF from baseline for patients prophylactically treated with the ACE inhibitor perindopril or the beta-blocker bisoprolol, respectively. In the placebo arm, LVEF declined by 5%. Overall, in the placebo arm 8 trastuzumab dose interruptions due to drops in LVEF versus 1 in each of the investigational arms (P <.05).

Added Chemo for Residual Disease

“This was a study that looked at drugs used for congestive heart failure. They used both a beta blocker and ACE inhibitor, and both drugs actually had an impact on the number of people who had to come off treatment,” Tripathy said. “This was the first time that there was any indication that you could actually prevent Herceptin cardiotoxicity.”A number of studies focused on neoadjuvant and adjuvant therapies for patients with early stage breast cancer. In phase III findings from the Japan Breast Cancer Research Group (Lee S-J, et al. SABCS; abstr S1-07), the addition of capecitabine to adjuvant therapy reduced the risk of disease recurrence by 30% and prolonged survival by 40% for patients with residual HER2-negative breast cancer following neoadjuvant chemotherapy and surgery.

After 5 years of follow-up, the DFS rate with capecitabine was 74.1% versus 67.6% with standard therapy alone (HR, 0.70; P = .00524). The 5-year overall survival (OS) rate for patients receiving capecitabine was 89.2% compared with 83.9% for those in the standard therapy arm (HR, 0.60; P <.01).

“If you give capecitabine after patients have had surgery but did not respond, you can actually lower the risk of mortality,” Tripathy said. “This was the first time that post-neoadjuvant chemo–additional chemo–was shown to help outcomes. This has generated a lot of interest.”

The study was designed to follow patients for 5 years. At this follow-up, based on the benefit seen with the addition of capecitabine to standard adjuvant therapy, an independent data monitoring committee recommended the discontinuation of the study. Subset analyses exploring the impact of hormonal therapy on outcomes are currently being conducted for OS.

Neoadjuvant Platinum-Based Therapy

“Additional treatment after chemo with capecitabine is immediately actionable and is something that needs to be discussed with patients,” suggested Tripathy.For patients with triple-negative breast cancer (TNBC), studies focused on optimizing neoadjuvant treatments, specifically with platinum-based regimens. In a collection of studies, neoadjuvant carboplatin was found to favorably impact DFS while improving pathologic complete response (pCR) rates.

In the phase II GeparSixto trial (von Minckwitz G, et al. SABCS; abstr S2-04), the addition of carboplatin improved the pCR rate from 36.9% to 53.2% (P = .005) in patients with TNBC. There was a significant improvement in DFS with the addition of carboplatin to standard chemotherapy compared with controls (85.8% vs 76.1%; HR, 0.56; P = .0350).

Immunotherapy on Horizon

“There are data now that show that in the preoperative neoadjuvant setting, the number of people that achieve a complete pathologic response is clearly higher with the use of platinums,” said Tripathy. “We don’t have data yet from direct randomized trials showing that the survival endpoint is improved, but there was, at the last ASCO meeting, some data presented on one of the two major studies but not on the other showing an improvement in disease-free survival.”A number of studies demonstrated intriguing findings for immune checkpoint inhibition in breast cancer at the 2015 SABCS. As single-agents, the PD-L1 inhibitor avelumab and the PD-1 inhibitor pembrolizumab (Keytruda) showed consistent response rates that were more pronounced in TNBC. Moreover, the combination of the PD-L1 inhibitor atezolizumab (MPDL3280A) and nab-paclitaxel (Abraxane) demonstrated high response rates.

“I think we should have a read out on some of the large pivotal trials for immunotherapy in triple-negative breast cancer within the next year or so,” said Tripathy. “I think the first approval of immunotherapy in breast cancer is about a year or two on the horizon.”

In the phase Ib avelumab trial (Dirix LY, et al. SABCS; abstr S1-07), after a median follow-up of 10 months, the objective response rate (ORR) in patients with PD-L1-expressing metastatic breast cancer was 33.3%. In patients with PD-L1-positive TNBC, the ORR was 44.4% with avelumab. Across the full study population, which included PD-L1-negative patients, the ORR was 4.8% (95% CI, 2.1-9.2).

In the phase Ib KEYNOTE-012 trial that explored pembrolizumab (Rugo HS, et al. SABCS; abstr S5-07), the ORR was 12% in PD-L1—positive patients with ER-positive, HER2-negative advanced breast cancer. At a median follow-up of 7.3 months, the ORR was comprised of all partial responses and no complete responses. The median time to response was 8 weeks and the median duration of response has not yet been reached, ranging from 8.7 to >44 weeks.

“The number of responses are small but intriguing, because some seem to be prolonged remissions. That's generated a lot of interest,” said Tripathy. Commenting on how immunotherapy will be applied in the future, he said “I see it in combinations with chemo, or right after chemo, but by itself alone there may be a role.”

In the phase Ib study exploring atezolizumab plus nab-paclitaxel (Adams S, et al. SABCS; abstr P2-11-06), the confirmed ORR was 66.7% in patients with metastatic TNBC. In the second-line setting, the confirmed ORR was 25% and in the third-line and beyond the ORR was 28.6%. Across the full trial, the ORR was 41.7%.

When including responses that were not yet confirmed on a second scan, the ORR was 70.8%, which included a complete response rate of 4.2%. In patients with PD-L1—positive TNBC, the ORR was 77.8% and the stable disease rate was 22.2%. In those with unknown biomarker status, the ORR was 75%, which included 1 complete response and 2 patients with progressive disease. In the PD-L1—negative group, the ORR was 57.1% and the stable disease rate was 42.9%.

“I think for the single-agent group of patients it is going to be important to see what will be the identifiers of people who respond, its not clear if you need PD-L1 expression or not,” said Tripathy. “I think there could be an alone indication in refractory patients, if we know who to treat, and then earlier treatment in combination with chemo.”

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