January 2018 Edition Vol.12, Issue 1

An Enhanced Understanding of Immunotherapy in Breast Cancer Emerges

By Wayne Kuznar

At the 40th San Antonio Breast Cancer Symposium (SABCS), several presentations supported a high prevalence of tumor infiltrating lymphocytes (TILs) and a high level of PD-L1 expression as correlates of response to immunotherapy in breast cancer. This evidence suggests a role for immune checkpoint blockade as monotherapy or in combination in the metastatic setting of human epidermal growth factor (HER)2-positive or triple negative breast cancer (TNBC).

Immunotherapy in earlier lines of treatment is tantalizing, as responses have been higher in patients with previously untreated metastatic breast cancer compared with heavily pretreated patients. The higher level of TILs found in the primary versus the metastatic setting suggests that responses may be superior with earlier treatment.


Biomarkers Correlate with Response

The prognostic value of TILs has been established in patients with HER2-positive breast cancer and TNBC “who have a large amount of lymphocytes infiltrating the tumor [and who] seem to have much better outcomes overall,” said Justin Balko, PharmD, PhD, leader of molecular oncology, Center for Cancer Targeted Therapies, Vanderbilt-Ingram Cancer Center, Nashville.

The level of TILs in the primary breast cancer prior to neoadjuvant chemotherapy was a strong predictor of patients who would achieve a pathologic complete response to an anthracycline plus taxane in patients with these breast cancer subtypes in the previously reported GeparSixto trial, he noted.

Patients with TILs tend to have high expression of PD-L1, a weaker marker of response to treatment, on their TILs, said Sherene Loi, MD, associate professor, Peter MacCallum Cancer Center, Melbourne, Australia.

“It certainly seems to be the TIL infiltrate that probably enriches for response to a PD-1 inhibitor on its own” or in combination, she said. “By the time [a patient] gets to the advanced stage and after multiple lines of treatment, [she] actually has a low level of T cell infiltrate in the metastatic lesion, for whatever reason…tumor burden, immunosuppression, or multiple lines of treatment.”

At SABCS, Dr. Loi presented results from PANACEA,1 a phase 1b/2 study in the metastatic HER2-positive setting that demonstrated the efficacy of pembrolizumab combined with trastuzumab in patients who developed resistance to trastuzumab and were positive for PD-L1 expression. The data also confirmed the role of stromal TILs as a biomarker predictive of response.

The lower level of TILs in metastatic breast tumors compared with primary tumors “reduces [the] chance of response to pembrolizumab as monotherapy,” she said. “We don’t know yet if chemotherapy in addition to pembrolizumab can change that tumor microenvironment, but certainly I think that earlier lines you go, the more chance you’re going to have of existing effective anti-tumor immunity that can be reactivated with the addition of pembrolizumab.”

Some patients maintain a degree of anti-tumor immunity even after many lines of treatment, and can still experience durable benefit from pembrolizumab, as was demonstrated in the PANACEA study.

PANACEA was a single-arm study of 58 patients with advanced HER2-positive breast cancer that enrolled two cohorts: one cohort of patients with PD-L1-positive tumors and a second cohort with PD-L1-negative tumors. The primary endpoint was the objective response rate (ORR) by RECIST1.1 criteria in the PD-L1-positive cohort. All patients received prior trastuzumab and prior anthracycline/taxane chemotherapy. The median time from diagnosis of metastatic disease to enrollment was 40 months.

Phase 1b was a dose-escalation portion of the trial in six patients with PD-L1-expressing tumors. Phase 2 comprised 40 patients in the PD-L1-positive cohort and 12 in the PD-L1-negative cohort. Tumors were assessed for PDL1 status and for the quantity of TILs.

PANACEA met its primary endpoint with the required number of prespecified responses. In the PD-L1 cohort, the ORR was 15.2% and the disease control rate, which included stable disease of 6 months or more, was 24%. In the PD-L1-negative cohort there were no objective responses.

In the PD-L1-positive cohort, the median duration of disease control in the patients who experienced an objective response or stable disease was 11.1 months. Five patients continued treatment at the time of data reporting with no progression. Of these, three patients have completed 2 years of pembrolizumab, said Dr. Loi.

The study confirmed that higher TIL levels were associated with an increased chance of response, and a TIL level as low as 5% could predict for a higher response. The median level of TIL infiltration in the metastatic tumor was 1%.

“This is 20 times less than what we observed in primary HER2-positive breast cancer,” said Dr. Loi. “However, we did notice a significantly higher TIL level in the PD-L1-positive cohort, as well as a significantly higher TIL level in patients who achieved an objective response… also, in those who achieved disease control.”


Durable Activity with Checkpoint Monotherapy

A follow-up of first-line pembrolizumab monotherapy in patients with PD-L1-positive, metastatic TNBC showed a continuation of durable anti-tumor activity in the full 84 patients enrolled in this cohort of the open-label, phase 2 KEYNOTE-086 trial.2

Among the first 52 patients enrolled in this cohort, the ORR with pembrolizumab at 200 mg every 3 weeks was 23.1%, as previously reported.

The update presented at SABCS by Sylvia Adams, MD, Director of clinical research, Breast Cancer Disease Management Group, New York University, showed that the ORR was maintained at 23% and the response duration was clinically meaningful at 10.4 months. The median overall survival (OS) was a promising 19.1 months, and OS was longer in patients whose best response was a complete response (CR), partial response, or stable disease. Responders had a higher level of TILs than the nonresponders. The rate of treatment-emergent adverse events of any grade was 63%.

Data with atezolizumab monotherapy in patients with metastatic TNBC, presented at the 2017 meeting of the American Association for Cancer Research, Washington, D.C., suggested that PD-L1 expression on immune cells in the tumor microenvironment is important for response.3

With pembrolizumab, “it appeared that stromal TILs were associated with response, particularly in the first line setting.” In contrast to the atezolizumab study, in which PD-L1 expression on tumor lymphocytes and macrophages correlated with response, this correlation did not seem to exist in KEYNOTE-086 of pembrolizumab monotherapy.

Elizabeth Mittendorf, MD, PhD, professor, Department of Breast Surgical Oncology, MD Anderson Cancer Center, Houston, summarized what is known about checkpoint inhibitor monotherapy to date in metastatic breast cancer.

“It appears that the responses are best when the agents are administered in the first line,” she said. “For those who do respond, responses appear to be quite durable. Biomarkers for these studies remain somewhat elusive.”


Immunotherapy Combinations: Which Ones Work Best?

Another focus of interest at the symposium was the choice of agent to combine with checkpoint blockade. The use of chemotherapy has been proposed to leverage chemotherapy-induced immunogenic cell death, said Dr. Mittendorf.

Sara Tolaney, MD, MPH, associate director of clinical research, Breast Oncology, at the Dana-Farber Cancer Institute, Boston, presented results from the phase 1b/2 ENHANCE trial,4 in which the use of eribulin mesylate in combination with pembrolizumab was explored in patients with metastatic TNBC who received zero to two lines of prior systemic therapy for metastatic disease.

There were no dose-limiting toxicities in phase 1b. The phase 2 dosages chosen were eribulin, 1.4 mg/m2 on days 1 and 8, and pembrolizumab, 200 mg on day 1 of a 21-day cycle.

The ORRs were 29.2% in patients who received no prior lines of therapy and 22.0% in those who received one to two prior lines of systemic therapy. “One thing that I thought was quite interesting about the data was the overall survival rate of 17.7 months, which is longer than what we’ve seen in trials that looked at eribulin as monotherapy, suggesting that there is something to this combination,” said Dr. Mittendorf.

The combination of olaparib and durvalumab resulted in an 80% disease control rate (DCR) at 12 weeks in an open-label phase 2 basket study that included 25 patients who had locally advanced or metastatic HER2-negative breast cancer and a deleterious germline BRCA and were naïve to immunotherapy or a poly (ADP-ribose) polymerase (PARP) inhibitor.5

The rationale for PARP inhibition in this setting is that inhibition of PARP in tumor cells that carry a germline BRCA mutation results in accumulating DNA damage and genomic instability. “The thought would be that accumulating DNA damage has the potential to modify tumor immunogenicity,” Dr. Mittendorf said.

Greater DNA damage leads to a greater number of mutations, which are recognized as foreign, thereby promoting a T-cell response. In addition, PARP inhibition has been shown to upregulate PD-L1 expression in breast xenograft models, lending support to a PARP inhibition/Immunotherapy combination.

As reported by Susan Domchek, MD, Basser professor in oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, the DCR with the combination of olaparib and durvalumab at 28 weeks, a secondary endpoint, was 48%.

The ORR in this trial was 67% in patients with either zero or one prior line of therapy, decreasing to 20% (1 of 5) in those receiving two prior lines and 0% (0 of 2) in patients receiving three or more prior lines of therapy. The median progression-free survival and OS had not yet been reached at data cut-off at 6 months. Among the 21 patients with archival samples available, no significant differences in levels of PD-L1 expression in immune cells or tumor cells according to response were observed.



  1. Loi S, et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive advanced breast cancer: results from the PANACEA study (IBCSG 45-13/BIG 4-13/KEYNOTE-014). 2017 San Antonio Breast Cancer Symposium; abstract GS2-06.
  2. Adams S, et al. KEYNOTE-086 cohort B: Pembrolizumab monotherapy for PD-L1-positive, previously untreated, metastatic triple-negative breast cancer (mTNBC). 2017 San Antonio Breast Cancer Symposium; abstract PD6-10.
  3. Schmid P, et al. Atezolizumab in metastatic TNBC (mTNBC): Long-term clinical outcomes and biomarker analyses. 2017 American Association for Cancer Research; abstract 2986.
  4. Tolaney SM, et al. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. 2017 San Antonio Breast Cancer Symposium; abstract PD6-13.
  5. Domchek SM, et al. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC). 2017 San Antonio Breast Cancer Symposium; abstract PD6-11.

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