Path to importance of PD-L1 status in breast cancer

Triple-negative breast cancer is the most likely of the three clinically relevant breast cancer types to be inflamed, or “hot,” with HER2-positive breast cancers just behind them, Dr. Leisha Emens said, noting they tend to have high numbers of CD3-positive T cells. At the other end of the spectrum are ER-positive luminal breast cancers, which tend to be devoid of T cells and are “cold,” she said.

The T cells in the tumor microenvironment of triple-negative and HER2-positive breast tumors are poised to respond to immune checkpoint blockade. ER-positive breast tumors lacking T cells are not likely to respond to immunotherapy agents because “there’s no gas in the tank,” as she put it.

A large body of data suggests that breast tumors with poor prognostic factors—including those that are ER- and PR-negative, of high grade, or lymph-node–positive—tend to be associated with higher T cell infiltrates at diagnosis, Dr. Emens said. Studies also have found higher numbers of CD8-positive TILs and a higher ratio of “good” CD8-positive T cells to “bad” FOXP3-positive T cells predict better clinical outcomes with immunotherapy, including a complete pathologic response to neoadjuvant therapy and longer disease-free and overall survival, except for ER-positive breast cancers.

To give a sense of the difference in the prevalence of the PD-L1 biomarker between triple-negative and ER-positive breast cancer, Dr. Emens discussed results from two phase one studies with the anti-PD-1 checkpoint inhibitor pembrolizumab. Patients were selected for both studies based on PD-L1 expression within the tumor microenvironment.

In the TNBC study, 58 percent of the 111 patients screened had PD-L1-positive tumors. In the 27 patients who underwent treatment with pembrolizumab, a response rate of almost 19 percent was achieved, including one complete response and several partial responses (Nanda R, et al. J Clin Oncol. 2016;34[21]:2460–2467). In contrast, in the ER-positive breast cancer study, of the 248 tumors screened, only 19.4 percent were PD-L1-positive. And of the 20 patients who received pembrolizumab, there was a response rate of 12 percent, with no complete responses and three partial responses (Rugo HS, et al. San Antonio Breast Cancer Symposium, 2015).

“This illustrates the differences in immunobiology between triple-negative breast cancer and ER-positive breast cancer, but shows there is potential for response if the preexisting immunobiology is there with this agent.”

In another study, Dr. Emens and her colleagues tested atezolizumab in 115 patients with advanced metastatic TNBC. Most patients were heavily pretreated before receiving atezolizumab, with only 17 percent of patients having had no prior treatment for metastatic disease (Emens LA, et al. JAMA Oncol. 2019;5[1]:74–82). Sixty-three percent of patients enrolled in the phase 1A study were PD-L1-positive and 33 percent PD-L1-negative.

The median duration of response was 21 months. Median progression-free survival was 1.4 months by response evaluation criteria in solid tumors, or RECIST, and 1.9 months by immune-related RECIST—not terribly impressive, Dr. Emens said. The overall response rate by RECIST, which included complete and partial responses, was 10 percent, and increased to 13 percent by immune-related RECIST.

PD-L1-positive expression in tumor-infiltrating immune cells of at least one percent was associated with a better outcome. Patients with PD-L1-positive tumors had a median overall survival of 10.1 months compared with six months in those with PD-L1-negative tumors. One-year OS for PD-L1-positive patients was 44 percent compared with 32 percent for PD-L1-negative patients. OS rates for PD-L1-positive patients at two and three years were 25 percent and 21 percent respectively.

The small number of patients who received atezolizumab as a first-line treatment had better outcomes with regard to OS (median 17.6 months) than the groups of patients who received atezolizumab second-line or later (7.3 months). The one-year OS rate for first-line patients was 59 percent and for second-line or greater, 37 percent.

The data also show that patients who had a complete or partial response to single-agent atezolizumab tend to do quite well: 100 percent of patients who had an objective response by RECIST were alive at one and two years, and even out to three years if the objective response rate was by immune-related RECIST. “For these patients lucky enough to respond to this therapy, it can be quite transformative for them,” Dr. Emens said.

PD-L1 and stromal TILs are likely to be imperfect biomarkers, she said, and the context in which they’re found matters. She discussed a phase two study (KEYNOTE-086) of single-agent pembrolizumab in patients with TNBC that consisted of two cohorts: cohort A enrolled patients previously treated for metastatic disease whose tumors expressed any level of PD-L1, while cohort B enrolled patients previously untreated for metastatic disease who were PD-L1-positive. The 52 first-line PD-L1-positive patients from cohort B had a response rate of 23 percent, which was similar to the response rate seen in the first-line setting with single-agent atezolizumab in the phase 1A study. In the previously treated patients in cohort A who had any level of PD-L1 expression, response rates ranged from four percent to 10 percent, depending on the level of expression, findings similar to those in the phase 1A study. Patients treated first line tended to have more TIL than patients in later lines.

While these studies provided preliminary evidence that therapy with immune checkpoint inhibitors can play a role in treating breast cancer, results from the randomized, double-blind phase three IMpassion130 trial “bring a potentially effective targeted therapy to the treatment armamentarium for this group of patients,” Dr. Emens said.

The IMpassion130 trial compared atezolizumab plus nab-paclitaxel with placebo plus nab-paclitaxel in patients with inoperable locally advanced or metastatic TNBC who had not received prior treatment for metastatic disease. Previous chemotherapy was allowed if it had been administered at least 12 months before this trial.

Patients were stratified by whether they had liver metastases, prior treatment with taxane, and PD-L1 status on immune cells. PD-L1 positivity on immune cells was defined as levels of one percent or more, with 41 percent of enrolled patients PD-L1-positive by this definition and 14 percent having PD-L1-positive expression at five percent or more. While PD-L1-positive expression wasn’t required for eligibility, the researchers analyzed the possible association of this biomarker with clinical benefit.

The findings revealed that the atezolizumab plus nab-paclitaxel combination led to significantly longer progression-free survival than was seen with placebo plus nab-paclitaxel in both the intention-to-treat population and the PD-L1-positive subgroup. In the PD-L1-positive subgroup, median PFS was longer by 2.5 months in the atezolizumab group than in the placebo group (7.5 months versus five months, respectively), and median OS was 10 months longer at the interim analysis (25 months versus 15.5 months).

No treatment effect was seen in progression-free or overall survival with the addition of atezolizumab to nab-paclitaxel in patients who were PD-L1-negative, Dr. Emens said. The addition of atezolizumab did not compromise the dose intensity of nab-paclitaxel.

Dr. Emens and colleagues analyzed other biomarkers that could be reflective of preexisting immunobiology and associated with clinical benefit from anti-PD-L1/PD-1 checkpoint inhibitors. They evaluated PD-L1 expression on tumor cells using the Ventana SP142 immunohistochemical assay, which was also used to evaluate immune cells, intratumoral CD8-positive T cells by IHC (Dako clone C8/144B) and stromal TIL using H&E, and BRCA1/2 mutation status using the FoundationOne assay.

“As long as patients had PD-L1 expression on immune cells at levels of one percent or more,” Dr. Emens said, “they derived clinical benefit for progression-free and overall survival. So the one percent cutoff appears to define a threshold above which patients can respond.”

Patients with CD8-positive tumors derived clinical benefit only if their tumors were also PD-L1 immune cell positive, she said, adding that the same is true for stromal TIL. And there was no association of benefit with the presence of a BRCA1 or 2 mutation unless the tumor was PD-L1 immune cell positive.

The immunobiology of patients seems to change dramatically after first-line therapy, Dr. Emens said. After that, patients are much less likely to be PD-L1-positive and their tumors are much less likely to contain TIL.

“All of this data taken together,” she said, “strongly support testing patients for their PD-L1 immune cell status when they are newly diagnosed with metastatic or unresectable locally advanced triple-negative breast cancer to determine if they might benefit from atezolizumab with nab-paclitaxel.” 

Mary Jane Friedrich is a writer in Lake Forest, Ill.