Immunotherapy Active in Early Stage Triple Negative Breast Cancer

Liam Davenport

September 29, 2019

BARCELONA, Spain — New hope for patients with triple negative breast cancer (TNBC) has been raised with results showing that immunotherapy has activity in early stage disease, after they were raised last year — and then subsequently dashed — by results with immunotherapy in the metastatic setting.

TNBC accounts for 15% of breast cancer cases, but unlike other types of breast cancer, the only medical treatment is chemotherapy, so the disease represents an "unmet medical need," commented Fabrice André, MD, PhD, professor in the Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.

Within this context, the new results "could have a major impact on treatment for these patients," he said in a statement.

The new results, presented here at the European Society for Medical Oncology (ESMO) 2019 annual meeting, show that adding immunotherapy to chemotherapy in patients with early stage TNBC substantially increases the likelihood that patients will have no residual disease by the time they undergo surgery.

Dr Peter Schmid

Peter Schmid, MD, PhD, clinical director of St Bartholomew's Breast Cancer Centre, Barts Health NHS Trust, London, UK, and colleagues conducted the phase 3 KEYNOTE-522, which added the immune checkpoint inhibitor pembrolizumab (Keytruda, Merck) to chemotherapy, the current standard of care.

A pathological complete response (pCR), a recognized surrogate for overall survival, occurred in almost 65% of patients given pembrolizumab plus chemotherapy versus only 51% of those given chemotherapy alone, Schmid reported.

The benefit was seen in both patients who were positive and negative for programmed death ligand 1 (PD-L1) expression, with similar increases in pCR rates in both groups.

There was even a hint that event-free survival rates were higher with immunochemotherapy than chemotherapy, at a 37% improvement among patients given pembrolizumab on top of chemotherapy, although the relatively short follow-up of only 15 months means the result should be interpreted with caution, Schmid said.

At an ESMO press conference where the results were highlighted, Schmid said that neoadjuvant chemotherapy is "the highest bar in terms of pCR rates," and the addition of immunotherapy to that chemotherapy "resulted in a statistically significant and, in my opinion, clinically meaningful increase in pCR rates."

He added that there was a "favorable trend for event-free survival compared to chemotherapy alone at this very early time...but of course subsequent data will be presented relatively soon."

He told Medscape Medical News: "I would assume in the next few months we will see stronger and then, likely my opinion, significant data on event-free survival."

"Then, I think it will be very difficult not to incorporate immune therapy into a neoadjuvant treatment regimen, if we show we significantly increase the pCR rates but we also reduce recurrences, which are very closely linked with survival in triple negative breast cancer," he said.

If approved in this setting, he believes the combination of pembrolizumab and chemotherapy "could become a standard of care."

Commenting for ESMO, Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug Development at the European Institute of Oncology, Italy, told the press conference that the increased pCR rate with combined immunochemotherapy is "really a breakthrough result" because of its implications for overall survival.

Examination of the baseline biopsies and residual tumor tissue in nonresponders will offer an opportunity to "better identify those patients who will more likely respond to immunotherapy," as well as "better understand the mechanism of resistance," he added.

Immunotherapy in Metastatic TNBC

This is not the first time that data on the use of immunotherapy in TNBC have been presented, although previous studies have focused on the metastatic setting.

At ESMO 2018, there were some overenthusiastic reporting that led to accusations of "hype" of early data from IMpassion130 on the use of the anti-PD-L1 drug atezolizumab (Tecentriq, Genentech) in previously untreated metastatic TNBC.

The results showed that adding atezolizumab to chemotherapy was associated with a 20% improvement in progression-free survival over placebo, rising to 38% among PD-L1 positive patients.

However, delegates at the American Society of Clinical Oncology (ASCO) 2019 annual meeting, were told this did not lead to a significant overall survival benefit, despite second interim results indicating atezolizumab plus chemotherapy led to a numerical increase in median overall survival over placebo in PD-L1 positive patients.

Looking at the results from KEYNOTE-522 and IMpassion130 in the round, Curigliano told Medscape Medical News that, in the metastatic setting, "it is quite clear there is a subpopulation of patients that will derive more benefit [from immunotherapy], and this population is PD-L1 positive."

"So, we need to select patients according to the expression of this target," he said.

However, "in the early breast cancer setting, this is not so clear," noting that the new results showed no difference in pCR between PD-L1 positive and negative tumors.

"I believe that here we don't have to select according baseline expression of PD-L1 because I am quite sure that, following exposure to chemotherapy, you increase PD-L1 expression and, for sure, you will derive more benefit," Curigliano commented.

He summarized: "We have two different settings in which immunotherapy works, but we need to better figure out how to select patients in the early breast cancer setting...because these are toxic drugs."

Schmid told the press conference that, although TNBC is "very difficult to treat," patients with early disease who achieve a pCR with chemotherapy prior to surgery have a long-term benefit.

He said a previous meta-analysis indicated patients who had a pCR after neoadjuvant chemotherapy had a "massively longer" recurrence-free survival, at a hazard ratio of 0.24, and experienced an overall survival benefit, at a hazard ratio of 0.16, versus patients that did not have a pCR.

Schmid said that "to set the scene, in the past we gave anthracyclines and taxanes and we achieved this pCR in about 40% of patients; if we added in platinum, we achieve a pCR in around 50% to 52% of patients."

He also noted that "both the US Food and Drug Administration and European Medicines Agency have said that we can use pCR as an endpoint for accelerated approval in the neoadjuvant setting, but we obviously have to demonstrate the longer-term benefit in terms of really reducing recurrences."

Study Details

For the KEYNOTE-522 study, 1100 patients with newly diagnosed TNBC were randomized (2:1) to pembrolizumab or placebo in addition to chemotherapy, which consisted of four cycles of paclitaxel plus carboplatin and four cycles of doxorubicin or epirubicin plus cyclophosphamide.

Following surgery, patients continued with pembrolizumab or placebo for a further nine cycles, or until recurrence or unacceptable toxicity.

In all, 784 patients were randomized to pembrolizumab and 390 patients to placebo, and the median follow-up was 15.5 months.

Among 602 patients evaluable for pCR, the team found that the addition of pembrolizumab to chemotherapy was associated with a significant increase in the rate for pCR over placebo, at 64.8% versus 51.2%, or a mean difference of 13.6% (P = .00055).

Stratifying patients by PD-L1 status indicated that the immunotherapy-chemotherapy combination was effective in both PD-L1 positive and negative patients.

Schmid showed that, among PD-L1 positive patients, adding pembrolizumab to chemotherapy was associated with a pCR rate of 68.9% versus 54.9% with placebo, a mean difference of 14.2%.

In PD-L1 negative patients, pembrolizumab plus chemotherapy was associated with a pCR rate of 45.3% versus 30.3% with chemotherapy alone, a mean difference of 18.3%.

There was also a signal for an improvement in event-free survival with pembrolizumab plus chemotherapy, although Schmid pointed out that a median follow-up period of 15.5 months was too short at this stage to draw any definitive conclusions.

He nevertheless said that pembrolizumab plus chemotherapy was associated with an event rate of 7.4% versus 11.8% for placebo plus chemotherapy, at an event-free survival rate at 18 months of 91.3% and 85.3%, respectively.

In terms of safety, the two regimens were broadly comparable, with 76.8% of patients treated with pembrolizumab plus chemotherapy experiencing grade 3–5 treatment-related adverse events during the neoadjuvant phase versus 72.2% for chemotherapy alone.

Treatment-related adverse events that led to death occurred in 0.3% of patients in both groups, and adverse events that led to discontinuation of any drug were observed 24.5% of patients with pembrolizumab and 13.1% of those taking placebo.

In the adjuvant phase, treatment-related adverse event rates were far lower, with 5.7% of patients treated with pembrolizumab experiencing a grade 3–5 event versus 1.9% of those given placebo.

Treatment-related adverse events leading to discontinuation were seen in 3.3% of those treated with pembrolizumab and 1.3% of those given placebo, and events leading to death occurred in 0.2% and 0.0% of patients, respectively.

Interaction Between Immunotherapy and Chemo

Schmid told the press conference it is not surprising that chemotherapy and immunotherapy should work together to improve response rates in TNBC.

"If you look across different cancers, we see there's a clear interaction between chemotherapy and immune therapy."

Chemotherapy, he explained, destroys cancer cells, which leads to the release and shedding of antigens, which the immune system can then detect.

It also "disrupts the structure of a cancer, making it easier for the immune cells to get in."

Consequently, "on many levels, chemotherapy can facilitate for the immune system to recognize cancer," Schmid said. "If you then boost the immune response by giving immune therapy, we have a synergistic activity and that's what we see across multiple tumor types, including breast cancer."

Discussing why combination therapy was effective in both PD-L1 positive and negative patients, he said: "One of the things we know is the tumor biology is very dynamic and when you start giving chemotherapy — a PD-L1 negative tumor may turn into a PD-L1 positive tumor within a few weeks."

"I think this dynamic process, this plasticity of tumors, is something we will take into consideration when we analyze the data in more detail," he said.

The study was funded by MSD. Schmid has received honoraria from Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Puma, Celgene; been an advisor/consultant for Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Puma, Celgene; received research grant/funding (institutional) from AstraZeneca, Genentech, Roche, OncoGenex, Novartis, Astellas. Spouse is a consultant for Genentech/Roche. Curilagno has been a speaker/consultant/served on advisory boards for MSD, Mylan, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, Seattle Genetics, NanoString, Roche; has been a speaker and writer for Novartis, Bristol-Myers Squibb, Scientific Affairs Group Ellipsis; has institutional financial interests (Phase I-II studies) with Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, Bristol-Myers Squibb, Merck Serono, MSD, Janssen Cilag, Philogen, Bayer, Medivation, Medimmune, Bayer; is a member of the executive board of EUSOMA; a member of scientific committee of Europa Donna; a member of scientific committee of Fondazione Beretta; and a member of the executive board of Lega Italiana Lotta ai Tumori (national public agency).

ESMO 2019. Presented September 29, 2019. Abstract LBA8_PR.

For more from Medscape Oncology, join us on Twitter and Facebook.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.