Rugo Sets the Stage for a Busy Year in Breast Cancer

Hope S. Rugo, MD, FASCO

Hope S. Rugo, MD, FASCO, describes working in medical oncology as a “tapestry” of experiences. In her case, it’s a very rich, complicated piece of art.

The 2020 Giants of Cancer Care^® award winner in the education category is at the forefront of the exploration and development of novel targeted therapies and immunotherapy for patients with breast cancer, including combinations that may overcome resistance, and of strategies to alleviate adverse effects of cancer treatment. She serves in leadership roles for several collaborative clinical investigations and is a noted lecturer at conferences throughout the world.

Through it all, Rugo prizes her relationships with patients. She maintains an active clinical practice at the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, where she is a professor in the Department of Medicine and the director of breast oncology and clinical trials. At UCSF, she leads the Breast Forum, a discussion platform for patients, families, and caregivers.

“It’s that tapestry that really creates this rich experience. I have had amazing interactions with patients who were remarkable and courageous—individuals who I feel really taught me a lot about life and gave me lessons that I brought back to other patients,” Rugo said in a recent interview with OncLive News Network^®. “I continuously learn from my patients and I love those interactions. Breast oncology, in some ways, is amazing because we can know an individual for many, many years and see them quite frequently; we know a lot about those patients and their families and how they’re dealing with these incredible challenges.”

Getting Ready for Miami

Rugo will join other leading breast cancer experts in translating her vast clinical knowledge for oncology specialists at the virtual 38th Annual Miami Breast Cancer Conference^® (MBCC), which Physicians’ Education Resource^®, LLC (PER®) is hosting March 4 to 7, 2021. PER^® named Rugo as its 2020 Educator of the Year in recognition of the role she plays in sharing her insights with the cancer care community.

Patrick I. Borgen, MD, chair of the Department of Surgery and head of Maimonides Breast Center at Maimonides Cancer Center, both at Maimonides Medical Center in Brooklyn, New York, serves as program chair for MBCC. Rugo is cochairing the conference with Anees B. Chagpar, MD, MBA, MSc, MPH, a professor in the Department of Surgery at Yale School of Medicine in New Haven, Connecticut, and Debu Tripathy, MD, professor and chairman of the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

The MBCC agenda always features important new data and expert insights on treatment approaches across the care spectrum and is updated after the San Antonio Breast Cancer Symposium (SABCS 2020) to present the latest information to attendees.

“There are just so many things going on that are really exciting right now in breast cancer,” Rugo said. “Miami Breast is great because it includes the new data in surgery, in radiation oncology, and in medical oncology, and both early-stage and metastatic disease.”

One of the hallmarks of the conference is the give-and-take between speakers and audience members, which helps to provide valuable perspective on the latest data. MBCC focuses not only on the latest data, but also on how to apply that data in the clinic.

“We do have selected debates about controversial areas,” Rugo said. “We’re going to talk about where we want to de-escalate treatment, where we want to escalate it, and how we’re using our increasing knowledge of cancer biology to apply this [information].

“We talk a lot about how [treatment] impacts the patient. What are the impacts…in terms of fertility? We’ve talked about cardiac effects, and patient-reported outcomes, how we treat patients who are older versus younger,” she continued. “We really try to cover all of the very clinically pertinent information and the information that’s come out of the most recent presentations and publications. And then there’s the ability to discuss this and ask questions with the presenters, which is, I think, really great.”

Rugo will be putting into perspective the evolving treatment landscape for patients with estrogen receptor–positive, high-risk, early-stage breast cancer and will present data on novel oral therapies. She expects that recent findings involving antibody-drug conjugates (ADCs), tyrosine kinase inhibitors (TKIs), CDK4/6 inhibitors, and the use of circulating tumor DNA as a predictive biomarker will be key points of discussion.

“There have been so many exciting studies presented this year which are practice changing that I think the Miami Breast meeting is a perfect time to really put this all together in a clinically applicable state,” she said. “And by being virtual, you’ll have access to everyone, and in some ways it’s even easier to attend.”

Looking Forward to 2021

Rugo is anticipating a busy year in breast cancer research, with investigators building upon many recent advancements. She said that noteworthy findings likely to change practice this year and beyond include research presented at SABCS 2020 into the clinical utility of the Oncotype DX Breast Recurrence Score test, immunotherapy in neoadjuvant and metastatic settings, and emerging novel therapies.

Her own research led to a significant development when the FDA approved margetuximab-cmkb (Margenza) in combination with chemotherapy for adults with metastatic HER2-positive breast cancer who have previously received 2 or more antiHER2 regimens, at least one of which for metastatic disease, in December 2020.

Rugo was the principal investigator for the phase 3 SOPHIA trial (NCT02492711), which showed that the Fc-engineered monoclonal antibody plus chemotherapy reduced the risk for disease progression or death by 24% compared with trastuzumab (Herceptin) plus chemotherapy. The median progressionfree survival (PFS) was 5.8 months (95% CI, 5.5-7.0) in the margetuximab-cmkb arm compared with 4.9 months (95% CI, 4.2-5.6) with the trastuzumab regimen (HR, 76; 95% CI, 0.59–0.98; P = .033).^1,2

Investigators observed an objective response rate (ORR) of 22% in the margetuximab arm versus 16% with trastuzumab. Drug maker MacroGenics plans to release overall survival (OS) data in the second half of 2021. The company said that margetuximab is the first HER2-targeted therapy to demonstrate improved PFS compared with trastuzumab in a head-to-head phase 3 clinical trial.

ADCs and TKIs

In the past 13 months, the FDA has granted accelerated approvals for 2 novel ADCs: fam-trastuzumab deruxtecan-nxki (Enhertu), for patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2- based regimens in the metastatic setting³; and sacituzumab govitecan-hziy (Trodelvy), for patients with metastatic triple-negative breast cancer (TNBC) who have received at least 2 prior therapies for metastatic disease.⁴

In December 2019, the FDA approved trastuzumab deruxtecan based on findings from the DESTINY-Breast01 trial (NCT03248492), in which the agent demonstrated an ORR of 60.3% (95% CI, 52.9%-67.4%), with a 4.3% complete response (CR) rate and a 56% partial response rate among 184 patients. The median duration of response (DOR) was 14.8 months (95% CI, 13.8-16.9).³

In updated results presented at SABCS 2020, the median DOR expanded to 20.8 months. The estimated 12- and 18-month overall survival (OS) rates were 85% (95% CI, 79%-90%) and 74% (95% CI, 67%-80%), respectively. The median PFS was 19.4 months (95% CI, 14.1-not estimable [NE]), and the preliminary median OS, although still immature, was 24.6 months (95% CI, 23.1-NE).⁵ In April 2020, the FDA approved sacituzumab govitecan based on findings from the phase 1/2 IMMU-132-01 trial (NCT01631552), which showed an ORR of 33.3% (95% CI, 24.6%-43.1%) with a median DOR of 7.7 months (95% CI, 4.9-10.8).⁴

Survival data from the phase 3 ASCENT trial (NCT02574455), presented at the European Society for Medical Oncology Virtual Congress 2020, showed that sacituzumab govitecan improved median OS by more than 5 months compared with chemotherapy (12.1 vs 6.7 months; HR, 0.48; 95% CI, 0.38-0.59; P < .0001). Median PFS for participants who received sacituzumab govitecan was 5.6 months (95% CI, 4.3-6.3) compared with 1.7 months (95% CI, 1.5-2.6) for patients who had chemotherapy (HR, 0.41; 95% CI, 0.32-0.52; P < .0001).⁶

The ADC also demonstrated an ORR of 35% versus 5% with physician’s choice of chemotherapy. Ten (4%) patients in the experimental arm had CRs compared with 2 (1%) in the control group.⁶

Further, the FDA also approved tucatinib (Tukysa), a HER2-directed TKI, in combination with trastuzumab and capecitabine in April 2020, for patients with advanced unresectable or metastatic HER2-positive breast cancer. The approval includes patients with brain metastases who have received at least 1 prior anti–HER2-based regimen in the metastatic setting.⁷

The agency based its decision on results from the HER2CLIMB trial (NCT02614794), in which the tucatinib-containing combination demonstrated a median PFS of 7.8 months (95% CI, 7.5-9.6) compared with 5.6 months (95% CI, 4.2-7.1) for patients who received placebo plus standard therapy (HR, 0.54; 95% CI, 0.42-0.71; P < .00001). The median OS was 21.9 months (95% CI, 18.3-31.0) with the addition of tucatinib versus 17.4 months (95% CI, 13.6-19.9) with standard therapy alone (HR, 0.66; 95% CI, 0.50-0.87; P= .00480).⁷

At SABCS 2020, investigators reported that the tucatinib regimen reduced the risk of deterioration of health-related quality of life in patients with brain metastases by 49% versus standard therapy (HR, 0.51; 95% CI, 0.28-0.93).⁸

“We have ADCs that are changing care for HER2-positive and for triple-negative disease with trastuzumab deruxtecan and sacituzumab govitecan. We have now a very potent and less toxic oral TKI, tucatinib, which has been combined with capecitabine and trastuzumab and results in not only improved PFS but improved OS in the metastatic setting and in patients with active brain metastases—very exciting data that have led to new studies,” Rugo said.

“We’re going to see data in the next year about the efficacy of these ADCs in other populations, such as patients with newly defined HER2-low disease—not HER2 positive but not zero by IHC [immunohistochemistry]—and also the ADC sacituzumab govitecan-hziy in [hormone receptor]–positive disease. There are, I think, really intriguing studies that will potentially allow us to further expand the use of this highly effective therapy,” she said.

The adverse event profile of a new therapy also must be taken into consideration, Rugo noted. “It is always important to understand toxicity with novel agents,” she said. “Trastuzumab deruxtecan has a relatively novel toxicity that is worth mentioning as it is so important for clinicians to recognize and understand. Interstitial lung disease [ILD] or pneumonitis can be seen with this ADC, and the mortality in the phase 2 trial was 2.7%. Current guidelines provide careful and detailed recommendations for managing this toxicity—holding the ADC for grade 1 asymptomatic ILD seen only on imaging, and permanently discontinuing along with steroid treatment for grade 2.”

CDK4/6 Inhibitors

According to Rugo, data presented at SABCS 2020 suggest an exciting future for CDK4/6 inhibitors. Results from an updated analysis of the phase 3 MONALEESA-7 trial (NCT02278120) showed that adding ribociclib (Kisqali) to endocrine therapy continued to significantly improve OS and delay subsequent chemotherapy compared with placebo, irrespective of endocrine partner, in pre- and peri-menopausal patients with hormone receptor–positive, HER2-negative breast cancer in combination with suppression of ovarian function.

At a median follow-up of 53.5 months (range, 46.9-66.4), median OS with ribociclib plus endocrine treatment was 58.7 months versus 48.0 months with placebo/endocrine therapy (HR, 0.763; 95% CI, 0.608-0.956), translating into a 24% relative reduction in risk of death with the CDK4/6 inhibitor.⁹

“We saw the updated survival data for MONALEESA-7, [which were] very impressive in young women,” Rugo said.

The conference also featured the primary outcome findings from monarchE (NCT03155997). The phase 3 trial tested the CDK4/6 inhibitor abemaciclib (Verzenio) in combination with standard-of-care endocrine therapy versus endocrine therapy alone in 5637 patients with HER2-positive, hormone receptor–positive, node-positive, high-risk early breast cancer.

Results showed that adding abemaciclib significantly improved invasive disease-free survival (iDFS) compared with standard endocrine therapy alone (HR, 0.713; 95% CI, 0.583-0.871; P = .0009) in the intention-to-treat population. This translated into a 28.7% relative reduction in the risk of developing an iDFS event.¹⁰

In further analysis of the study data, investigators suggested that high expression of Ki-67, a protein marker of cellular proliferation, potentially could be used in conjunction with clinicopathological features to indicate which patients have a greater risk of recurrence and might have the greatest benefit from the addition of the CDK4/6 inhibitor.

Although patients benefited from abemaciclib therapy regardless of Ki-67 expression, outcomes were worse for those with a high level, defined as 20% or greater on IHC testing. These patients had a lower rate of 2-year iDFS of 91.3% (95% CI, 88.9%-93.2%) compared with 94.7% (95% CI, 92.8%-96.1%) for patients with a Ki-67 low score.¹¹

The study marked the first time the prespecified threshold for high Ki-67 was used prospectively with a standardized assay in a phase 3 trial, investigators said. Rugo is excited about the potential for its use as a biomarker. “It’s not just clinical features, like stage and grade, but also Ki-67 is emerging as an incredibly important factor,” Rugo said. “I think this is likely to be practice changing in the next year.”

Targeted Therapy

Findings that Rugo and colleagues presented at SABCS 2020 for alpelisib (Piqray), a PI3K inhibitor, are likely to inform treatment choices for a subset of patients with hormone receptor–positive, HER2-negative progressive metastatic disease. In the ongoing phase 2 BYLieve trial (NCT03056755), investigators are evaluating alpelisib in patients with previously treated PIK3CA-mutant hormone receptor–positive, HER2-negative advanced breast cancer.¹²

The trial has 3 arms: cohort A, testing alpelisib plus fulvestrant (Faslodex) in patients whose immediate prior treatment was a CDK4/6 inhibitor plus an aromatase inhibitor (AI); cohort B, evaluating alpelisib plus letrozole in patients whose immediate prior treatment was a CDK4/6 inhibitor plus fulvestrant; and cohort C, testing alpelisib plus fulvestrant in patients who progressed on or after AI therapy and then received chemotherapy or endocrine therapy as their immediate prior treatment.¹²

Results were presented for 115 patients in cohort B, in which 82% of participants had progressed on prior AI therapy. A total of 46.1% of patients were alive without disease progression at 6 months per local investigator assessment (n = 53; 95% CI, 36.8-55.6), meeting the primary end point of the study. At a median follow-up of 15 months, the combination of alpelisib and letrozole led to a median PFS of 5.7 months (95% CI, 4.5-7.2).

“In this cohort, the majority of patients had previously been exposed to an AI and had had progression on that treatment, so this is really the most endocrine-resistant population that has been treated with alpelisib combined with an endocrine therapy,” Rugo said.

The median PFS, she noted, is “quite impressive” for a patient population treated with an AI after exhibiting resistance to an AI.

Making a Mark in the Field

The research Rugo presented at SABCS 2020 provides a glimpse at her expansive accomplishments as a clinical investigator, starting in the late 1980s while she was a hematology and oncology fellow at UCSF.

Over the years, she has served as the principal investigator in more than 60 clinical trials, many of which led to major discoveries. Specifically, Rugo led studies exploring the use of agents such as palbociclib (Ibrance) and abemaciclib, and was a member of the steering committees for multiple clinical trials including for the ABRAZO and EMBRACA studies (NCT02034916 and NCT01945775) evaluating the PARP inhibitor talazoparib (Talzenna) in patients with BRCA-mutant metastatic breast cancer.

In the immunotherapy field, Rugo was a primary investigator for the IMpassion130 trial (NCT02425891), which led to the March 2019 FDA approval of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) for patients with unresectable, locally advanced PD-L1–positive TNBC. This marked the first immune checkpoint inhibitor to be approved for the treatment of breast cancer.¹³

She also was on the steering committee for the KEYNOTE-355 trial (NCT02819518) testing pembrolizumab (Keytruda) plus chemotherapy for patients with TNBC and presented a subset update at SABCS 2020. The results of this trial led to FDA approval of pembrolizumab plus either nab-paclitaxel, paclitaxel, or gemcitabine with carboplatin for PD-L1–positive TNBC in November 2020.¹⁴

Rugo is actively involved in the multicenter adaptively randomized I-SPY 2 trial, where she is chair of the safety committee and serves on the novel agent committee, publishing the results of 1 of the first arms of the trial (paclitaxel plus veliparib-carboplatin).¹⁵

Rugo also has made relieving toxicities of cancer treatment part of her mission. She was the principal investigator for a study evaluating the DigniCap Scalp Cooling System, which uses scalp cooling technology to help prevent chemotherapy-related hair loss. In 2017, DigniCap became the first FDA-approved cooling cap for patients with solid tumors.¹⁶ She also led the 2017 SWISH trial (NCT02069093), which investigated a dexamethasone-based mouthwash that reduces stomatitis and mouth and lip inflammation in patients with metastatic breast cancer receiving treatment with everolimus (Afinitor). Findings showed that the oral solution reduced the severity of stomatitis, and the mouthwash has been used ever since.¹⁷

“These are projects we all have worked on together and as a community have been able to really make a difference for patients who are being treated with these agents— understanding the time course of toxicity,” she explained. “These have been really great to work on.”

One of Rugo’s lasting contributions to the field is likely to be in training junior faculty and helping patients and their families understand their options for treatment. She also runs UCSF’s Breast Forum, an open bimonthly evening educational session for patients with breast cancer and their families and friends.

Rugo is a master educator and clinician, according to Laura J. Esserman, MD, MBA, the 2018 Giants of Cancer Care^® award winner in the cancer diagnostics category. “Not only is she good at educating residents and other physicians and scientists, but she is fantastic at educating her patients about what their risks are, what their options are,” said Esserman, the Alfred A. de Lorimier Endowed Chair in General Surgery and director of the Carol Franc Buck Breast Care Center at UCSF Helen Diller Family Comprehensive Cancer Center. “She has that amazing talent for putting information together in such a way that people can make better decisions.”

According to Rugo, her experiences in medical education not only taught her how to convey information, but also help her better relate to her patients and colleagues. She considers herself “very fortunate” to have worked in the field, both nationally and internationally, and credits her career choice and focus to her mother, who died of breast cancer more than 20 years ago.

“That also gives you lots of ideas about clinical research and it keeps you in touch with the community at large,” she said. “Then you learn a lot about other cultures and how people manage different aspects of both cancer care and life and death issues as well—that’s been an amazing experience.”

References

1. FDA approves margetuximab for metastatic HER2-positive breast cancer. FDA. December 17, 2020. Accessed January 4, 2021. https://bit.ly/2JN7mYL
2. MacroGenics announces FDA approval of Margenza for patients with pretreated metastatic HER2-positive breast cancer. News release. MacroGenics, Inc. December 16, 2020. Accessed January 4, 2021. http://bit.ly/3gTMuLq
3. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA. December 20, 2019. Accessed December 29, 2020. https://bit.ly/3pvvRJ6
4. FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. FDA. April 22, 2020. December 29, 2020. https://bit.ly/37VcLWH
5. Modi S, Saura C, Yamashita T, et al. Updated results from DESTINY-Breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2-positive metastatic breast cancer. Poster presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Session PD3. https://bit.ly/38NIx7f
6. Bardia A, Tolaney SM, Loirat D, et al. ASCENT: a randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31(suppl 4):S1149-S1150. doi:10.1016/annonc/annonc325
7. Tukysa. Prescribing information. Seattle Genetics, Inc; 2020. Accessed December 29, 2020. https://bit.ly/34S6sl5
8. Wardley A, Mueller V, Paplomata E, et al. Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with stable and active brain metastases. Poster presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Session PD13. https://bit.ly/2KNAFuD
9. Tripathy D, Im SA, Colleoni M, et al. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2–) advanced breast cancer (ABC) treated with endocrine therapy (ET) ribociclib. Poster presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Session PD2. https://bit.ly/3pEMMJp
10. O’Shaughnessy JA, Johnston S, Harbeck N, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high-risk early breast cancer. Poster presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Session GS1. https://bit.ly/3mUziaw
11. Harbeck N, Johnston S, Fasching P, et al. High Ki-67 as a biomarker for identifying patients with high-risk early breast cancer treated in monarchE. Poster presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; Virtual. Session PD2. https://bit.ly/3aOJ6R4
12. Rugo HS, Lerebours F, Juric D, et al. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results. Poster presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Session PD2. https://bit.ly/34VjOg9
13. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. FDA. Updated March 18, 2019. Accessed January 10, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative 
14. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. FDA. November 13, 2020. Accessed January 10, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-pembrolizumab-locally-recurrent-unresectable-or-metastatic-triple
15. Rugo HS, Olopade OI, DeMichele A, et al; I-SPY 2 Investigators. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Eng J Med. 2016;375(1):23-34. doi:10.1056/NEJMoa1513749
16. FDA clears expanded use of cooling cap to reduce hair loss during chemotherapy. FDA. Updated March 28, 2018. Accessed January 10, 2020. https://www.fda.gov/news-events/press-announcements/fda-clears-expanded-use-cooling-cap-reduce-hair-loss-during-chemotherapy
17. Rugo HS, Seneviratne L, Beck JT, et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol. 2017;18(5):654-662. doi:10.1016/S1470-2045(17)30109-2