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Immunotherapy Regimens Yield Contrasting Results in Early Triple Negative Breast Cancer


SAN ANTONIO – Trials of two different immunotherapy regimens have returned contrasting results in the triple negative breast cancer molecular subgroup in presentations at the annual San Antonio Breast Cancer Symposium.

Though neither trial is mature enough to report on critical survival endpoints, one study did see early evidence of efficacy that could forecast survival results, while the other didn't. Results also didn't paint a clear picture for the impact of PD-L1 status in this setting, reinforcing the challenge oncologists who want to practice precision medicine face with immunotherapy biomarkers that continue to vary across different drugs, cancers, and clinical niches. 

One analysis from the KEYNOTE-522 trial found that the addition of the anti-PD-1 immunotherapy pembrolizumab (Merck's Keytruda) to neoadjuvant chemotherapy, with additional treatment as adjuvant therapy, increased the rates of pathologic complete response (pCR) in patients with TNBC, especially in patients with lymph node involvement.

In the other, from the NeoTRIPaPDL1 trial, investigators concluded that the addition of the anti-PD-L1 drug atezolizumab (Roche/Genenetech's Tecentriq) to neoadjuvant chemotherapy did not improve the rate of pathologic complete response when compared to chemotherapy alone, though that was not a primary endpoint of the study.

Researchers at the meeting put forward numerous hypotheses for why the two studies diverged in this way in their pCR results. 

One possibility may be that the two drugs are different. Pembrolizumab is a PD-1 inhibitor and atezolizumab is a PD-L1 inhibitor. Both affect the same biological pathway and have been "assumed to have the same effect at the end of the day … but there may be not so subtle differences," said Luca Gianni, president of the Fondazione Michelangelo in Milan and lead author of the atezolizumab report.

Columbia University Irving Medical Center oncologist Kevin Kalinski, acting as a discussant for the two trial presentations, also raised this possibility. "Blocking PD-1 [with pembrolizumab] blocks both PDL-1 and PDL-2, but [with atezolizumab] this allows PD-L2 signaling, and whether or not this is clinically significant, we'll see in future trials," he said.

"It's worth noting that in any solid tumor, there's never been direct comparisons," he added.

Spurring both neoadjuvant efforts that were presented at the meeting is the emerging success of immunotherapy drugs in treating advanced, metastatic cases of triple negative breast cancer, including the FDA approval earlier this year of atezolizumab in combination with nab-paclitaxel for certain advanced TNBC patients.

Also, according to researchers at the conference, small trials have recently begun to demonstrate that adding checkpoint inhibitors to neoadjuvant chemo is safe and promising for earlier-stage patients.

While the standard of care for early-stage TNBC remains neoadjuvant chemotherapy, researchers have been evaluating whether adding immunotherapy might help push more patients into a state of pathologic complete response and improve their rate of disease-free survival. 

Patients who show pCR after neoadjuvant chemotherapy are known to have a much lower risk of recurrence, but at most only about 50 percent achieve this state using current methods.

"There continues to be a significant need for new regimens that can increase the pCR rate and increase long-term, event-free survival," Peter Schmid, professor of cancer medicine at Barts Cancer Institute in London and principal investigator of KEYNOTE-552, said in a statement.

In KEYNOTE-552, Schmid and colleagues are examining the effect of adding pembrolizumab to neoadjuvant chemotherapy, and as an added adjuvant treatment, in patients with early-stage TNBC. 

The study enrolled 1,174 patients with previously untreated, non-metastatic, centrally confirmed TNBC. Patients were randomly assigned to receive either pembrolizumab plus chemotherapy or placebo plus chemotherapy. After neoadjuvant treatment, patients underwent definitive surgery and received radiation therapy as indicated.

After surgery, patients went on to adjuvant pembrolizumab or placebo until recurrence or unacceptable toxicity. Investigators plan to analyze if the immunotherapy confers benefits in terms of both pathologic complete response and, in the longer term, event free survival.

Some of the results from KEYNOTE-522 have already been shared, most recently at the European Society of Medical Oncology annual meeting this October. But the San Antonio update included new subgroup analyses of patients with lymph node involvement, which is known to confer added recurrence risk.

At ESMO, Schmid and colleagues reported that patients in the pembrolizumab plus chemotherapy arm had a significantly higher rate of pCR compared to patients in the chemotherapy alone arm (about 65 percent versus 51 percent) regardless of PD-L1 expression as calculated according to the so-called Combined Positive Score, or CPS, which relies on Agilent Technologies' Dako PD-L1 IHC 22C3 pharmDx assay.

CPS is calculated using the number of PD-L1 staining cells (tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, multiplied by 100. A sample is considered to be PD-L1-positive if the score is at least 1.   

The new data shared in San Antonio also showed that patients at higher risk of recurrence may be getting an even greater benefit than the overall population. Among those whose cancers had spread to the lymph nodes and who got pembrolizumab, almost 65 percent had a pCR compared to 44 percent in the chemotherapy-only arm. High rates of pCR were also observed in patients with stage III disease, also a known high-risk group.

According to Schmid, the results as a whole suggest that "adding pembrolizumab to neoadjuvant chemotherapy is beneficial for patients with the most aggressive disease and the highest unmet need."

That said, as reported at ESMO, the trial has recorded significant improvements in pCR for the immunotherapy arm across risk groups and cancer stages, regardless of PD-L1 status.

Although PD-L1 levels did appear to be associated with pCR —  patients with higher CPS saw higher pCR rates, reaching up to over 80 percent in the subset of pembrolizumab-treated patients with CPS over 20, for example — this trend line seems to hold true for chemotherapy-only treatment as well. In other words, the association is showing signs of being potentially prognostic, but not predictive for benefit from the immunotherapy strategy in particular.

This may seem counterintuitive considering that there has been a "clear difference in terms of benefit"  in the metastatic setting, Schmid said in his presentation. One factor that may explain this, he added, is an inherent biological difference between earlier-stage and metastatic triple negative breast cancers.

"My personal feeling is that tumor plasticity [and] dynamics in tumor biology, are very high in early disease," Schmid said. In early-stage cancer, patients who are PD-L1 negative before therapy may turn functionally positive as chemotherapy drives an influx of immune cells into the tumor, he explained. This plasticity, or ability for immune cells to get into a tumor gets lost over time, so the same wouldn't be seen in advanced disease. And this would then explain the demonstrated difference in responsiveness between baseline PD-L1 positive and negative patients in the later-stage setting.

The KEYNOTE investigators said that at their current analysis point — after 15 months of follow-up — they haven't yet met their predefined threshold for clinical significance, but they are seeing a "strong favorable trend for event-free survival. According to Schmid, the results "have the potential to be practice-changing."

While the followup time is short, he explained during his SABCS presentation that investigators are seeing a clear separation of curves in the KEYNOTE-522 data, with estimated event-free survival of 90.3 percent for the immunotherapy arm versus 85.3 percent for placebo.

In the NeoTRIPaPDL1 trial involving atezolizumab, meanwhile, preliminary pCR results were negative, though investigators said that they were not necessarily expecting to see any difference between study arms and have reason to believe that their regimen can show an impact on outcome without affecting this interim endpoint. 

In the Roche/Genentech trial, investigators have been testing the addition of the atezolizumab to neoadjuvant chemotherapy. The study enrolled 280 female patients with early-stage, high-risk and locally advanced or inflammatory TNBC. Patients were randomly assigned to receive neoadjuvant carboplatin and nab-paclitaxel with or without atezolizumab with the primary endpoint being five-year event-free survival and a secondary aim to study the rate of pathologic complete response.

Survival results are still to come, but for pCR, trial investigators reported that adding atezolizumab to neoadjuvant chemotherapy resulted in slightly higher rates of pathologic complete response after six months of treatment (43.5 percent versus 40.8 percent) though this was not statistically significant.

Among patients whose tumors tested positive for PD-L1 and who got atezolizumab, 51.9 percent had pCR compared to 48 percent of those in the chemotherapy only arm. Unfortunately, this difference was also not significant. 

Unlike the CPS assay used in the pembrolizumab trial, the atezolizumab study has employed the Ventana PD-L1 (SP142) Assay, which was developed as a specific companion for that drug. The scoring algorithm established for metastatic TNBC defines positivity as being 1 percent or greater staining in tumor-infiltrating immune cells covering a certain amount of tumor tissue area.

Gianni stressed that the lack of a significant association for pCR in this first analysis of NeoTRIPaPDL1 should not necessarily mean that the trial will not show a positive association in outcomes. "Our observations may indicate that there is no therapeutic benefit ... or it may simply mean that any beneficial effects of the combination will be seen in the long term," he said. 

During a press conference at the meeting, Gianni further explained that while pCR achievement has a clear link to outcomes where chemotherapy is concerned, the same has not been true for other adjuvant/neoadjuvant drugs like endocrine therapies.

Kalinski echoed this. "The FDA's released guidance for accelerated approval [states that] pCR is likely to serve as a predictor for clinical benefit in particular for high-risk patients, such as those with triple negative breast cancer … but on an [individual] trial level, we've seen that some agents lead to a higher pCR without necessarily improving clinical outcomes," he said, citing the example of neoadjuvant bevacizumab (Genentech's Avastin).

The goal for NeoTRIPaPDL1 investigators now, Gianni said, is to continue toward their primary outcome endpoint, and to mine through their tissue and blood biomarker data to see if there are any factors that can stratify or define groups for which there may have been a difference in either pCR or outcomes with the addition of atezolizumab. In addition to PD-L1, the study is analyzing other biomarkers, including lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA.

"We need to ask ourselves, 'Is PD-L1 status the best predictor for checkpoint inhibitor response" in this setting? Kalinski said summing up the results. Although it has proved predictive in some tumor types, in breast cancer, retrospective multi-omics analyses have found that PD-L1 protein expression lags other factors, such as T cell abundance and tumor mutation burden, he added.  

Schmid said additional biomarker analyses are also going on now for KEYNOTE-522, including measurement of tumor infiltrating lymphocytes and BRCA1/2 mutation status.

Posing the question of whether the positive results for the KEYNOTE-522 regimen portend a new standard of care if the treatment is approved, Kalinski concluded that "these are exciting data, both in pCR, and early event-free survival." 

"But there is a risk," he said, "of overtreatment, as well as potentially long-term and potentially incurable toxicities in patients with curable disease … [so] we need predictors," he added, which PD-L1 does not look like its gearing up to be in this setting.

One clear takeaway from the data so far is that PD-L1 does seems to confer a value in terms of higher pCR rates, he said. But it shows this trend with chemotherapy, as well, meaning it "is not identifying who specifically is benefiting from adding checkpoint inhibition."

"The take home is that this regimen will likely be practice changing in some patients and with the absence of having a predictor, the benefit may most outweigh the risk in patients with high clinical risk, such as what we saw in the lymph node-positive data presented today," he added.

For the atezolizumab regimen, "it will be interesting to see … whether the old rules of pCR still apply [or] whether despite the fact that we're not seeing an improvement in pCR … there will still be improvement in event-free survival."