Kinjal Parikh, PharmD BCOP
Associate Director, Clinical Strategy
Medscape Oncology
New York, NY

The 42nd annual San Antonio Breast Cancer Symposium (SABCS), held December 10–14 in San Antonio, TX, brought together an anticipated 7,500 attendees from 90 different countries to highlight and celebrate the year of advances in breast cancer treatment. This year has been notable for clinical breakthroughs across multiple tumor subtypes, including hormone receptor (HR)–positive, human epidermal growth factor receptor (HER) 2–positive, and triple-negative breast cancers, and data from these studies will likely influence the treatment algorithms and clinical decision making for teams in this upcoming year.

Dr. Nadia Harbeck’s summary of the conference in the special session Friday night titled “View from the Trenches: What Will You Do on Monday Morning?” highlighted some of the impactful data releases from the meeting, and Dr. Sara Hurvitz’s “Year in Review of Metastatic Breast Cancer” provided a 30,000-foot view of the gains this year in meaningful outcomes reported from clinical trials, novel therapeutic mechanisms, and hope for patients traditionally underrepresented in clinical trials.

HR-Positive Patients
The American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) meetings held earlier in 2019 highlighted some impressive survival benefits of CDK4/6 inhibitors, and though cross-trial comparisons do not represent head-to-head data, many of the responses for patients treated with CDK4/6 inhibitors far exceed the benefits in progression-free survival (PFS) rates and overall response rates (ORRs) from endocrine therapy alone or chemotherapy. The question about the role of chemotherapy, especially in patients with symptomatic disease, remains, as well as whether replacing chemotherapy with CDK4/6 inhibitors is the superior treatment.

Riding the wave of positive data from the Young-PEARL trial in premenopausal patients demonstrating PFS benefit compared to capecitabine in a phase 2 trial,¹ further follow-up at SABCS was given to another randomized phase 3 trial. The PEARL trial was an important trial evaluating palbociclib plus exemestane or fulvestrant in a 1:1 comparison to capecitabine for HR-positive metastatic breast cancer patients whose disease progressed on prior aromatase inhibitor therapy.² The trial did not meet its primary endpoints for superiority in PFS for both coprimary objectives of

• palbociclib plus fulvestrant versus capecitabine regardless of ESR1 mutational status
• palbociclib plus endocrine therapy versus capecitabine in ESR1 wild-type tumors.

More adverse events were recognized and more treatment discontinuations occurred in patients on the capecitabine arm.

HER2-Positive Patients
The bulk of impressive data at the meeting came from the HER2-positive subtype, with subsequent publications following the oral presentations. The key trials include the HER2CLIMB, SOPHIA, and DESTINY-Breast 01, representing the agents tucatinib, margetuximab, and trastuzumab deruxtecan, respectively.

Dr. Rashmi Murthy and colleagues published the results of HER2CLIMB in the New England Journal of Medicine (NEJM) on December 11.³ This trial compared tucatinib plus trastuzumab plus capecitabine to placebo plus trastuzumab plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and TDM-1. Patients with previously treated stable brain metastases and those with brain metastases (treated or not) not requiring immediate local therapy were also included. Forty-eight percent of patients had a presence or history of brain metastases in the tucatinib arm versus 46% in the placebo arm. PFS was 7.8 months with tucatinib-based therapy versus 5.6 months with placebo (p < .001; hazard ratio [HR] = 0.54). ORR for tucatinib-based therapy was 41% versus 23% for placebo. In a specific consideration of patients with brain metastases, the PFS benefit remained statistically significant at 7.6 months versus 5.4 months (p < .001; HR = 0.48), favoring tucatinib-based therapy. Overall survival (OS) in the overall population was 21.9 months versus 17.4 months (p = .005; HR = 0.66), resulting in both PFS and OS benefit for the tucatinib arm at the time of publication.

Dr. Hope Rugo followed up on outcomes of the SOPHIA trial at SABCS.⁴ This trial compared chemotherapy with margetuximab or trastuzumab in pretreated patients with HER2-positive metastatic breast cancer. The trial continued to show significant PFS (5.7 months with margetuximab versus 4.4 months with trastuzumab [p = .0006, HR 0.71]) and ORR and clinical benefit response rates but did not meet OS benefits at the second interim analysis: 21.6 months with margetuximab versus 19.8 months with trastuzumab (p = .326, HR = 0.89). Final OS results are pending release in late 2020. This trial did highlight a pioneering novel therapeutic option evaluating an engineered trastuzumab that alters the Fc receptor affinity.

Dr. Shanu Modi and colleagues also published their results from the DESTINY-Breast 01 trial in NEJM on December 11.⁵ Trastuzumab deruxtecan, a novel antibody-drug conjugate, was evaluated in patients with HER2-positive disease who had received a median of 6 prior lines of therapy ranging from 2 to 27 lines of therapy. ORR was found to be 60.9%, with complete response rate of 6% and duration of response lasting 14.8 months. Response was seen not only in the patients with HER2-positive breast cancer but also in the 16% of patients with IHC1+ or 2+ FISH positivity. Median PFS was 16.4 months, and OS was not yet reached. A notable adverse event was interstitial lung disease resulting in grade 5 toxicity in 4 patients.

Triple-Negative Patients
Finally, immunotherapy outcomes were important in a review of the progress made in breast cancer treatment. Immunotherapy first made headway in treating breast cancer through the IMpassion130 trial leading to the U.S. Food and Drug Administration’s approval of atezolizumab plus nab-paclitaxel in the metastatic setting. At this year’s SABCS, immunotherapy was explored in earlier settings of disease.

NeoTRIPaPDL1 evaluated neoadjuvant chemotherapy with or without atezolizumab in early high-risk or locally advanced unilateral breast cancer followed by surgery and four cycles of an anthracycline regimen.⁶ Fifty-six percent of patients were PD-L1-positive. The pathologic complete response (pCR) was 43.5% for the atezolizumab arm and 40.8% for the control arm (p = 0.55, NS). ORR was 76.1% with atezolizumab versus 68.3% without.

KEYNOTE-522 explored chemotherapy with or without pembrolizumab neoadjuvantly followed by pembrolizumab or placebo adjuvantly for patients with early triple-negative disease.⁷ Data from ESMO previously demonstrated pCR of 64.8% for the pembrolizumab arm versus 51.2% for the control arm (p = .00055). Updated results discussed at this meeting showed benefit in patient subgroups with lymph node disease as well as stage 3 disease.

Though speculations were made about the differences in the trial designs that led to the different statistical outcomes, immunotherapy is here to stay for patients with triple-negative disease and may expand beyond the metastatic setting.

Pharmacologic Advances
In addition to data releases on therapies with novel engineering of antibodies such as margetuximab or antibody-drug conjugate formulations like trastuzumab deruxtecan, new classes of treatment such as PI3K inhibitors have been added to the treatment paradigm of breast cancer. In addition, novel administrations of chemotherapy showing that oral paclitaxel with encequidar was superior to IV paclitaxel in a phase 3 trial for patients with metastatic breast cancer were highlighted at this meeting.⁸

Many exciting changes lie ahead in the treatment paradigm of breast cancer and span not only clinical advances with novel agents but also novel mechanisms and formulations.

This year’s abstracts can be found at https://www.abstractsonline.com/pp8/#!/7946.

SABCS 2020 will be held December 8–12. For more information visit https://www.sabcs.org/.

References

1. Park YH, Kim TY, Kim GM, et al. Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019 Oct 24 pii: S1470-2045(10)30565-0. doi:10.1016/S1470-2045(19)30565-0. [Epub ahead of print].
2. Martin M, Zielinski C, Ruiz-Borrego M, et al. Results from PEARL study (GEICAM/2013-02_CECOG/BC1.3.006): A phase 3 trial of palbociclib (PAL) in combination with endocrine therapy (ET) versus capecitabine (CAPE) in hormone receptor (HR)-positive/human epidermal growth factor receptor (HER) 2-negative metastatic breast cancer (MBC) patients (pts) whose disease progressed on aromatase inhibitors (AIs). Presented at 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS2-07.
3. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2019 Dec 11. doi:10.1056/NEJMoa1914609. [Epub ahead of print].
4. Rugo HS, Im S, Cardoso F, et al. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival analysis. Presented at 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-02.
5. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2019 Dec 11. doi:10.1056/NEJMoa1914510. [Epub ahead of print].
6. Gianna L, Huang C, Egle D, et al. Pathologic complete response (pCR) to neoadjvaunt treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michelangelo randomized study. Presented at 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS3-04.
7. Schmid P, Park YH, Ferreira M, et al. KEYNOTE-522 study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early triple-negative breast cancer: pathologic complete response in key subgroups and by treatment exposure, residual cancer burden, and breast-conserving surgery. Presented at 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS3-03.
8. Umanzor G, Rugo H, Cutler DL, et al. Oral paclitaxel with encequidar: the first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: a phase III clinical study in metastatic breast cancer. Presented at 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS6-01.