Keytruda-chemo Combo Best for Clearing Tumors in Early TNBC, Latest Trial Data Show

Adding the immunotherapy Keytruda (pembrolizumab) to chemotherapy increases the number of women with early triple-negative breast cancer who clear all signs of cancer, and tends to prolong survival without complications or symptoms, according to the latest results from the KEYNOTE-522 trial.

“The data suggest that the improved pathological complete response with pembrolizumab translates into fewer recurrences [the return of cancer],”  Peter Schmid, MD, the medical oncologist who presented the study, said in a press release.

The results were shared at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain, on Sept. 29, in a presentation titled, “Phase 3 study of pembrolizumab (pembro) chemotherapy (chemo) vs placebo (pbo) chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC).”

Triple-negative breast cancer (TNBC) accounts for 15% of breast cancers; it is the most aggressive type of breast cancer and is more common among young women.

“It represents an unmet medical need, since the only approved medical therapy at early stages of the disease is chemotherapy,” said Fabrice André, MD, PhD, professor at the Institut Gustave Roussy, a leading immunotherapy center in Paris, France.

The treatment that provides better chances of pathological complete response, meaning the disappearance of all signs of cancer cells, consists of chemotherapy followed by surgery to remove the tumor.

Women with a complete response have an 85–90% probability of being cured, while those with residual tumor tissue have a 40–50% chance of seeing their cancer recur, which happens often within a period of three years.

The ongoing KEYNOTE-522 Phase 3 trial (NCT03036488) is testing if adding immune therapy with Merck‘s Keytruda to chemotherapy, prior to surgery, could improve pathological complete response and event-free survival (time lived without complications or symptoms), in a safe manner in women with early TNBC.

In the first part of the study, 1,174 participants were assigned randomly to neoadjuvant therapy with Keytruda or placebo, in combination with chemotherapy — four cycles of Taxol (paclitaxel) plus Paraplatin (carboplatin), followed by four more cycles of Adriamycin (doxorubicin), or Ellence (epirubicin), plus Cytoxan (cyclophosphamide).

Treatment was given prior to surgery, and as injections into the vein, for five to six months. Neoadjuvant therapy is given to reduce the tumor burden before it’s removed by surgery.

After surgery, participants continued to adjuvant treatment with Keytruda, or a placebo for about 27 weeks (nine cycles) or until recurrence or unacceptable toxicity. Adjuvant treatment is given after the primary therapy to lower the risk that the cancer will come back.

The results presented at the ESMO Congress were collected after a median follow-up of 15.5 months. Among the first 602 patients assessed, Keytruda significantly increased the number of women who achieved a complete response, meaning they got fully cleared of cancer signs, from 51.2% in the placebo group to 64.8%.

“We found a 13.6% difference which is a clinically meaningful benefit,” said Schmid, who also is a professor at Barts Cancer Institute, Queen Mary University of London, in the U.K.

Compared with the overall study population, the benefit was slightly better in patients with tumors positive for PD-L1. In this case, the proportion of women attaining a complete response was 54.9% in the placebo and 68.9% in the Keytruda group.

Conversely, fewer women on the PD-L1-negative population responded to treatment — 30.3% in placebo versus 45.3% in the Keytruda group.

Testing for PD-L1 on cancer cells is used to predict how well a patient is likely to respond to some immune checkpoint inhibitors, like Keytruda. If cancer cells have a high amount of PD-L1, patients are more likely to benefit from this type of treatment.

Despite the differences between PD-L1-positive and negative patients, researchers were surprised by the poor predictive value of PD-L1 in this trial.

“This is probably because most early stage triple negative breast cancers express some degree of PD-L1, sometimes below the predefined cut-off of positivity. The role of chemotherapy as a sensitizer for anti-PD-1 in PD-L1-low early stage triple negative breast cancer should also be explored,” said  André.

As TNBC is an aggressive type of cancer that often comes back early on, the investigators conducted a preliminary analysis to see how long patients stayed without complications and symptoms of the disease, a measure called event-free survival.

The results showed that those on Keytruda tended to live more time without signs of disease return (although the trend was not statistically significant).

“These are preliminary data, but they provide a strong sign that the addition of immune therapy to neoadjuvant chemotherapy prevents breast cancer recurrence. If we prevent recurrence, we cure more patients, but we need longer-term data for confirmation,” Schmid said.

Across the whole study, serious or worse side effects occurred in 78% and 73% of the Keytruda and placebo groups, respectively. Death rates with each group were 0.4% and 0.3%.

However, many of the side effects were caused by the intensive chemotherapy regimens. Unwanted effects possibly related to immune therapy occurred both in patients taking Keytruda (42%) and patients on placebo (21%).

“Immune therapy added some side-effects to chemotherapy but there were no new safety signals,” Schmid added.

Keytruda is approved in the U.S. and Europe for the treatment of various solid tumors and certain blood cancers and used mainly for cancers that are advanced, have spread to other parts of the body (metastatic), or are not responding to other treatments. It is not approved for the treatment of women with breast cancer.

“This is a good situation to test whether the FDA will approve a drug for triple negative breast cancer based on pathological complete response. The combination of the anti-PD-1 monoclonal antibody pembrolizumab plus chemotherapy could become a standard of care if approved,” André said.

“The next step will be to define which patients are resistant and prioritize which targets should be hit in this population. We also have to determine the impact of this new class of drug on survivorship issues,” he added.