Top Developments in Breast Cancer Research Shape the MBCC Agenda

Debu Tripathy, MD

The breast cancer field is experiencing rapid advancements in the understanding of disease biology and the development of novel therapeutic strategies for several subtypes, with a clear direction toward personalized or precision medicine, according to Debu Tripathy, MD.

That means the experts who are sharing their insights at the 36th Annual Miami Breast Cancer Conference^® (MBCC) will have plenty to discuss throughout the 4-day gathering. Tripathy, one of the program cochairs for this year’s conference, reviewed key trends and developments, including some with the potential to change practice, in an interview in advance of the event.

During the past year, FDA decisions have expanded options for patients with breast cancer in several ways, through, for example, the approvals of the first and second PARP inhibitors for this tumor type, additional indications for CDK4/6 inhibitors, and 2 trastuzumab biosimilars (Table).

Tripathy, professor and chair of the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, emphasized some of the recent clinical findings that are shaping standards of care.

“It’s been a banner year for new drugs, new approvals, [and] new concepts,” said Tripathy. “The pace of development has really picked up. A lot of that is because we have newer technology to analyze these tumors at the genomic level, at the RNA level, [and] at the gene expression level with immunohistochemical tests and ‘multiplex/multiomics’ studies. It’s becoming much more feasible to do these very ambitious, multiparametric studies on multiple samples over time to really get a picture of what’s going on and to apply this information toward new and more innovative strategies. This is a consequence of having a much more robust set of tools to interrogate tumors.”

Table. A Timeline of Recent FDA Approvals in Breast Cancer

Early-Stage Breast Cancer

The knowledge gained thus far underscores the need to incorporate tissue collection and analysis into clinical trials for new drug regimens, Tripathy said. “It used to be that we studied the biology separately in the laboratory and then we developed treatments empirically,” he said. “But now that we’re starting to get more sophisticated drugs that work specifically in certain types of breast cancers, breast cancers are being increasingly segregated into different biologically and clinically relevant genotypes and phenotypes. The key thing is we have to study both clinical and biological outcomes at the same time.”Hormone Therapy in Premenopausal Women

In terms of hormonal therapy, long-term results of 2 large clinical trials, SOFT and TEXT, confirmed the benefit of adding ovarian function suppression to 5 years of tamoxifen or exemestane for premenopausal women with hormone receptor (HR)—positive breast cancer.

In SOFT, the 8-year disease-free survival (DFS) rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression. The 8-year rates of overall survival (OS) for the treatment arms were 91.5%, 93.3%, and 92.1%, respectively. The impact of ovarian suppression was greatest in patients with higher risk, such as those who required chemotherapy. The trial randomized 3047 patients, most of whom (84.9%) were HER2-negative, to 1 of the 3 treatment arms. Ovarian suppression consisted of triptorelin, bilateral oophorectomy, or ovarian irradiation.¹

In TEXT, 2672 patients were randomized to receive 5 years of triptorelin with either exemestane or tamoxifen, with bilateral oophorectomy or ovarian irradiation 6 months after starting triptorelin.

After a median follow-up of 9 years, investigators analyzed the combined population of the 2 studies and found that exemestane plus ovarian suppression resulted in an 8-year DFS rate of 86.8% compared with 82.8% with tamoxifen (hazard ratio, 0.77; 95% CI, 0.67-0.90; P <.001).¹ The DFS advantage with exemestane was greater compared with tamoxifen in patients who also received adjuvant chemotherapy because of a higher risk of recurrence, but with no difference in overall survival.

The findings “confirm that especially in high-risk patients, there is an added benefit of ovarian suppression,” Tripathy said. “That now has become a new standard of care and is incorporated into the most recent guidelines.”

Bone-Modifying Agents

The issues raised in these trials are more likely to affect younger women than older women; nearly 60% of the participants in SOFT and 68% of those in TEXT were between the ages of 40 and 49 years.The use of bone-modifying agents as adjuvant therapy for postmenopausal women with non-metastatic breast cancer is the subject of continuing debate, Tripathy noted. The population includes patients who have undergone menopause naturally or through ovarian suppression or ablation.

In 2017, ASCO recommended zoledronic acid (4 mg intravenously every 6 months) or clodronate (1600 mg/day orally) for postmenopausal patients who are candidates for adjuvant systemic therapy. Denosumab (Xgeva), a RANK ligand inhibitor, was described as a “promising” option with insufficient data for a recommendation.²

“We know that bisphosphonates can help reduce that risk of fracture, especially in people who have low bone density. However, there are some data suggesting that they also have an effect on actual recurrences, perhaps because the bone may serve as a reservoir for metastases,” Tripathy said. “That has never been shown in any given single trial, but it has been found in an overview analysis, and on that basis now several agencies are recommending the continuing use of bisphosphonates to lower the risk of recurrence.”

Avoiding Chemotherapy

The findings of the phase III TAILORx study demonstrate that adjuvant endocrine therapy alone is noninferior to adjuvant chemoendocrine therapy in patients with HR-positive, HER2-negative, node-negative, early-stage breast cancer who have an intermediate risk of distant recurrence based on the Oncotype DX Breast Recurrence Score test.

The results, presented at the 2018 ASCO Annual Meeting and published simultaneously online in the New England Journal of Medicine (NEJM),³ are expected to save thousands of women from overtreatment with chemotherapy. The noninferiority of endocrine therapy alone compared with endocrine therapy plus chemotherapy (hazard ratio, 1.08; 95% CI, 0.94-1.24; P = .26) met the trial’s primary endpoint.

“The randomized trials for the intermediate scores showed no real difference from adding chemotherapy to endocrine therapy,” Tripathy said. “Some patients under age 50 with hormone receptor—positive cancers with intermediate scores may benefit from chemotherapy, but by and large, we can omit treating patients with both intermediate and low scores.

“That accounts for anywhere from two-thirds to one-quarter to one-third of patients, so that’s an important new finding,” Tripathy added.

HER2-Positive Breast Cancer

In another significant development, findings from the phase III KATHERINE study showed that ado-trastuzumab emtansine ( T-DM1; Kadcyla) reduced the risk of invasive disease recurrence or death by 50% compared with trastuzumab (Herceptin) as an adjuvant treatment for patients with HER2-positive, early-stage breast cancer who had residual invasive disease following neoadjuvant therapy.

Results demonstrated that the 3-year invasive disease-free survival (iDFS) rate was 88.3% with T-DM1 versus 77.0% with trastuzumab, a 50% relative reduction in the odds of invasive recurrence. The iDFS benefit with T-DM1 was upheld across key patient subgroups, according to data presented at the 2018 San Antonio Breast Cancer Symposium and simultaneously published in NEJM.⁴

The findings “showed that TDM-1 was clearly a superior treatment for these patients and will also probably influence the standard of care,” Tripathy said. “This has not yet been formally approved by the FDA, but it’s expected that it will.”

The FDA is reviewing a supplemental biologics license application for T-DM1 as an adjuvant treatment in this setting under the agency’s Real-Time Oncology Review pilot program, which aims to expedite the development of new drugs.

CDK4/6 Inhibitors

Several sessions at MBCC will include discussion of treatment strategies for HER2-positive breast cancer, starting with the World Class Tumor Board mini symposium held on Thursday afternoon.The introduction of CDK4/6 inhibitors has changed the standard of care for patients with HR-positive, HER2-negative breast cancer, showing a doubling in time to progression when added to standard endocrine therapy in either first- or second-line therapy.

The FDA-approved class started with palbociclib (Ibrance) in 2015 and now includes ribociclib (Kisqali) and abemaciclib (Verzenio). Although palbociclib was initially approved for postmenopausal patients, the indications for CDK4/6 inhibitors are expanding to premenopausal populations.

In July 2018, the FDA approved up-front ribociclib for use in combination with an aromatase inhibitor (AI) for pre/perimenopausal or postmenopausal women with HR-positive/ HER2-negative advanced or metastatic breast cancer. The agency also approved the drug for use in combination with fulvestrant (Faslodex) for postmenopausal women in the frontline setting or after disease progression on endocrine therapy.

The approval for premenopausal patients is based on findings from the phase III MONALEESA-7 trial in which the combination of ribociclib and either tamoxifen or an AI (letrozole or anastrozole) resulted in a 10.8-month improvement in median progression-free survival (PFS) compared with placebo plus hormonal therapy (23.8 vs 13.0 months, respectively; hazard ratio, 0.55; 95% CI, 0.44-0.69; P <.0001).⁵

Tripathy, who is the lead investigator on the MONALEESA-7 trial, said a benefit with CDK4/6 inhibition has also been demonstrated in results from subsets of 2 other trials. “I think we now have solid evidence that we can treat premenopausal patients,” said Tripathy.

Immunotherapy

Next steps in the research include further identifying subsets of patients who are most appropriate for this therapeutic approach and improving the understanding of resistance mechanisms. “The CDK inhibitor story continues to evolve,” Tripathy said.Although the development of effective immunotherapy for patients with breast cancer has proved elusive in the past, recent clinical trial findings are generating excitement. In October, investigators reported positive findings for the combination of the PD-L1 inhibitor atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) in patients with triple-negative breast cancer (TNBC).

In the phase III IMpassion130 trial, the combination reduced the risk of progression or death by 38% compared with nab-paclitaxel alone in patients with PD-L1—positive metastatic TNBC, according to findings presented at the 2018 ESMO Congress.

Results of the co-primary PFS analysis in the PD-L1—positive population demonstrated a clinically meaningful median PFS of 7.5 months (95% CI, 6.7-9.2) with atezolizumab/nab-paclitaxel and 5.0 months (95% CI, 3.8-5.6) with chemotherapy (hazard ratio, 0.62; 95% CI, 0.49-0.78; P <.0001). Moreover, the 1-year PFS rates were 29% (95% CI, 22%-36%) and 16% (95% CI, 11%-22%) with atezolizumab/nab-paclitaxel and nab-paclitaxel, respectively. PD-L1 positivity was defined as at least 1% expression on tumor-infiltrating immune cells.⁶ Importantly, an impressive 9.5-month improvement in survival was seen in the PD-L1—positive subset.⁶

“It’s the first randomized trial to show a benefit of immunotherapy and, if the follow-up data hold up, an improvement in survival, specifically in patients with PD-L1 expression of 1% or more in immune cells,” said Tripathy.

New and Emerging Targeted Therapies

There are many ongoing trials testing immunotherapy in TNBC and other breast cancer types, raising the prospect of new drug approvals for this modality, Tripathy noted.Although therapies aimed at hormone and HER2 overexpression are long established in the breast cancer field, 2018 saw the introduction of molecularly targeted therapies. Olaparib (Lynparza), which had already been approved in ovarian cancer settings, gained an indication for germline BRCA-mutated, HER2-negative metastatic breast cancer after prior therapy. This was followed by the approval of a new PARP inhibitor, talazoparib (Talzenna), for a similar patient population.

In discussing other targeted therapy developments, Tripathy noted promising data for alpelisib (BYL719), a PI3K inhibitor. The addition of alpelisib to fulvestrant nearly doubled median PFS compared with the endocrine therapy alone in patients with HR-positive/ HER2-negative advanced breast cancer and a PIK3CA mutation, according to findings from the phase III SOLAR-1 study.

The median PFS by local assessment was 11.0 months (95% CI, 7.5-14.5) for those who received the alpelisib combination compared with 5.7 months (95% CI, 3.7-7.4) for those who received placebo plus fulvestrant. Those results, assessed after a median follow-up of 20 months, translated into a 35% reduction in the risk of progression or death, with a hazard ratio of 0.65 in favor of alpelisib (95% CI, 0.50-0.85; P = .00065). There was no advantage to alpelisib in median PFS in a separate cohort of patients without a PIK3CA mutation.⁷

These results are expected to strengthen the argument for genomic testing in metastatic breast cancer.

For HER2-positive breast cancer, novel antibodies, tyrosine kinase inhibitors ( TKIs), and antibody—drug conjugates (ADCs) are being developed.

In the TKI category, Tripathy pointed to tucatinib, an oral TKI that is being explored in combination with trastuzumab (Herceptin), which also targets HER2, plus capecitabine in patients with previously treated unresectable locally advanced or metastatic HER2-positive breast cancer in the HER2CLIMB trial (NCT02614794). The triplet regimen was associated with a 42% central nervous system response rate among patients with brain metastases in a small phase I study.⁸

In terms of ADCs, trastuzumab deruxtecan (DS-8201), a HER2-targeting agent, demonstrated an objective response rate (ORR) of 61.4% in a phase I study of patients with HER2-expressing metastatic breast cancers who had previously received T-DM1.⁹ Responses are also being seen in cases that are HER2-low (but negative by standard criteria). The drug is being developed under a breakthrough therapy designation for a similar patient population.

Sacituzumab govitecan, an ADC under study for metastatic TNBC, is also generating excitement. The drug links SN-38, an active metabolite of irinotecan, to a humanized immunoglobulin G antibody targeted against TROP-2, a glycoprotein expressed on more than 90% of TNBC tumors.

In phase I/II trial results, sacituzumab govitecan demonstrated an ORR of 33.3% in 108 patients with heavily pretreated metastatic TNBC. The clinical benefit rate, including stable disease for ≥6 months, was 45.4%. The median PFS was 5.5 months (95% CI, 4.1-6.3), and the median OS was 13.0 months (95% CI, 11.2-13.7).¹⁰

The FDA was evaluating the drug for an accelerated approval but issued a complete response letter on the application, citing “chemistry, manufacturing, and control matters,” according to Immunomedics, the company developing the agent. Immunomedics said the company would meet with the FDA to resolve the questions, with the goal of setting a timeline for the drug’s approval.

The potential for new drugs in several disease settings will be discussed during different presentations at MBCC.

References

1. Francis PA, Pagani O, Fleming GF, et al; the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122-137.doi: 10.1056/NEJMoa1803164.
2. Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35(18):2062-2081. doi: 10.1200/JCO.2016.70.7257.
3. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi: 10.1056/NEJMoa1804710.
4. von Minckwitz G, Huang C-S, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. New Engl J Med. 2019;380(7):617-628. doi: 10.1056/NEJMoa1814017.
5. Tripathy D, IM SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-915. doi: 10.1016/S1470-2045(18)30292-4.
6. Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi: 10.1056/NEJMoa1809615.
7. Andre&#769; F, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA3. cslide.ctimeetingtech.com/library/esmo/browse/search/2ByJ#2Ea3t0j5.
8. Lin N. Systemic therapy for breast cancer brain metastases. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract ES3-3. abstracts2view.com/sabcs18/view.php?nu=SABCS18L_9056INV&terms=.
9. 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. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD3-07. sabcs.org/Portals/SABCS2016/Documents/SABCS-2017-Abstracts.pdf.
10. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380(8):741-751. doi: 10.1056/NEJMoa1814213.

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