Immunotherapy Comes of Age in Breast Cancer

Hope S. Rugo, MD, FASCO

Breast cancer has historically been an immunologically cold disease, but recent and emerging data are carving out a space for several immunotherapies in the treatment paradigm. As the understanding of subtype response to treatment expands, so has exploration into antitumor immune response in patient subpopulations, especially in those with triple-negative breast cancer (TNBC).

"When IL-2 and interferon were being tested for melanoma and renal cell [carcinoma] the word on the street was that your body doesn’t see breast cancer cells as being foreign because you have breast cancer cells floating about anyway," said Hope S. Rugo, MD, FASCO, cochair of the 37th Annual Miami Breast Cancer Conference^® during a presentation. "But it turned out that, as we understood the biology of breast cancer and these more aggressive subtypes, that actually TNBC and then, next, most frequently, HER2-positive disease, particularly ER-negative/HER2-positive disease, had evidence of an immune response and what we found in analysis of large trials was evidence of an immune response as well as to some degree in the metastatic setting correlated to better outcome."

Rugo, a professor in the Department of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, traced the recent progress of immunotherapy trials in breast cancer and identified key focus areas for the future of immune checkpoint inhibition in early stage disease.

Determining whether it is possible to improve survival through first improving response to treatment came from subset analysis and checkpoint inhibitor studies designed to look at patient response when treated in the first-line setting. "Responses in patients [with PD-L1-positive disease] in the first-line setting were closer to 25%, so clearly something different was going on here biologically," said Rugo. "We understood that tumors become less immune sensitive or immunologically responsive over time, as they garner mutations and have genomic chaos with progression."

Rugo noted that this led investigators to go back to the immunity cycle and look for areas where augmentation was possible.

IMpassion130

The phase III IMpassion130 trial (NCT02425891) investigated whether the anti—PD-L1 monoclonal antibody atezolizumab (Tecentriq) in combination with nab-paclitaxel (Abraxane) would confer a consistent survival advantage for patients with PD-L1–positive, treatment-naïve, metastatic TNBC.¹

Patients were randomly assigned to receive nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 of a 28-day cycle with atezolizumab 840 mg (n = 451) on days 1 and 15 or with placebo (n = 451). Treatment was given until disease progression or unacceptable toxicity. Patients were assessed using the SP142 assay, which measures PD-L1 only in the immune cells surrounding and infiltrating the tumor. The results identified that 41% of the total population was PD-L1—positive (≥1% expression).

In the primary analysis, atezolizumab plus nab-paclitaxel resulted in a statistically significant progression-free survival (PFS) benefit in the intention-to-treat population compared with placebo plus nab-paclitaxel (HR, 0.80; 95% CI, 0.69-0.92; P = .0025) and demonstrated a trend toward improved overall survival (OS; HR, 0.84; 95% CI, 0.69-1.02; P = .0840).¹

Among patients with PD-L1—positive tumors, the addition of atezolizumab resulted in clinically meaningful improvements in both PFS (HR, 0.62; 95% CI, 0.49-0.78; P <.001) and OS (HR, 0.62; 95% CI, 0.45-0.86). There was no improvement in the patients with PD-L1—negative disease in PFS (HR, 0.93; 95% CI, 0.77-1.11) or OS (HR, 0.97; 95% CI, 0.78-1.20).

The FDA approved the combination in March 2019 based on the primary analysis of IMpassion130 results, which showed that atezolizumab/nab-paclitaxel reduced the risk for progression or death by 40% compared with nab-paclitaxel alone in patients with unresectable locally advanced or metastatic PD-L1—positive TNBC.²

In a posthoc analysis presented at the 2019 European Society for Medical Oncology, patients with PD-L1—positive tumors continued to show clinically meaningful improvements with the addition of atezolizumab in both PFS (HR, 0.63; 95% CI, 0.50-0.80) and OS (HR, 0.62; 95% CI, 0.54-0.93).³ "With longer follow up the survival improvement in patients who had IC+ disease was 7 months, very impressive," said Rugo. "It's the first treatment to improve survival other than chemotherapy for triple-negative, metastatic breast cancer."

"We know that our cancers respond less and have shorter duration of response as they progress through metastatic disease," Rugo said. Several studies have demonstrated a reduction in both expression of PD-L1 and TILs as tumors progress from early to late-stage disease. Moving therapy forward may lead to improved survival.

KEYNOTE-522

The KEYNOTE-522 trial (NCT03036488) examined neoadjuvant pembrolizumab (Keytruda) in early TNBC. In findings published in the New England Journal of Medicine, pembrolizumab plus platinum-containing chemotherapy extended the pathological complete response (pCR) rate by 13.6 percentage points (64.8% vs 51.2%) compared with chemotherapy alone.⁴

Patients were assigned pembrolizumab 200 mg every 3 weeks (n = 784) or placebo (n = 390). All patients received 4 cycles of carboplatin plus paclitaxel followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. Following surgery, adjuvant pembrolizumab was continued for 9 cycles or until disease recurrence or unacceptable toxicity.

In the PD-L1—positive group (n = 498), the pCR rate was 68.9% in the experimental arm compared with 54.9% in the placebo arm, respectively. In PD-L1–negative patients (n = 97), the pCR rate was 45.3% with pembrolizumab versus 30.3% with placebo.

SAFIR01-IMMUNO

In recent exploratory analysis from the phase II SAFIR01-IMMUNO trial, durvalumab (Imfinzi) as maintenance therapy, may improve outcomes compared with chemotherapy.

Among patients with TNBC (n = 82) in the SAFIR02 trial, the median OS was 21 months (95% CI, 16.6-27.0) with maintenance durvalumab compared with 14 months (95% CI, 9.0-16.3) with chemotherapy (HR, 0.54; 95% CI, 0.30-0.97; P = .0377). In those with PD-L1—positive disease across several breast cancer subtypes (n = 44), the median OS was 26 months with durvalumab (95% CI, 15.0–not reached [NR]) compared with 12 months (95% CI, 6.3–NR) with chemotherapy (HR, 0.42; 95% CI, 0.17-1.05; P = .0552).⁵

"In the group of patients who had triple-negative disease and in the group of patients who had PD-L1—positive breast cancer, most of whom had triple-negative disease, 52% versus 15% non–triple-negative, there seemed to be a marked improvement in overall survival, really quite dramatic," Rugo said. "These numbers are small, but it is quite encouraging that there may be a role for maintenance immunotherapy."

Future directions for the field include looking at novel combination strategies that may offer great promise. Explorations into benefit for HER2-positive and estrogen receptor—positive disease are also being actively explored. "Immunotherapy is a reality now for breast cancer," Rugo concluded.

References

1. 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.
2. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. FDA website. www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative. Updated March 9, 2019. Accessed March 6, 2020.
3. Rugo H, Loi S, Adams S, et al. Performance of PD-L1 immunohistochemistry assays in unresectable locally advanced or metastatic triple-negative breast cancer: post hoc analysis of IMpassion130. Presented at: 2019 European Society for Medical Oncology Annual Meeting; September 21-October 1, 2019; Barcelona, Spain.
4. Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810-821. doi: 10.1056/NEJMoa1910549.
5. Dalenc F, Bachelot T, Fllleron T, et al. Durvalumab compared to maintenance chemotherapy in patients with metastatic breast cancer: results from phase II randomized trial SAFIR02-IMMUNO. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS3-02.

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