New Hope in Triple Negative Breast Cancer With Immunotherapy

Liam Davenport

October 20, 2018

MUNICH — For the first time, immunotherapy has shown a survival benefit in breast cancer. The result was seen with the anti-programmed cell death ligand 1 (PD-L1) drug atezolizumab (Tecentriq, Genentech) used with chemotherapy in triple negative breast cancer in PD-L1-positive (PD-L1+) patients.

The results, from the IMpassion130 study, were presented here at the European Society for Medical Oncology (ESMO) 2018 Congress and simultaneously published in the New England Journal of Medicine.

The trial randomized over 900 women with triple negative disease to atezolizumab or placebo plus chemotherapy as first-line therapy.

Across the board, the addition of atezolizumab was associated with a 20% improvement in progression-free survival (PFS).

However, when the researchers looked at a subgroup of patients who were PD-L1+,  the addition of atezolizumab improved PFS by 38% and increased overall survival by the same percentage, offering patients an additional 10 months of life over those who received chemotherapy alone.

Peter Schmid, MD, PhD

The study was led by Peter Schmid, MD, PhD, clinical director of St. Bartholomew's Breast Cancer Centre, Barts Health NHS Trust, London, UK, and lead of the Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, UK.

At a press conference, he emphasized that not only was there a significant benefit in PFS with atezolizumab over placebo but there was also a "clinically meaningful benefit" in both PFS and overall survival in PD-L1+ patients.

Pointing out that 41% of the patients with triple negative breast cancer in the study were PD-L1+, Schmid said, "For me, this is, at the moment, clearly a PD-L1+ story," adding that there is "no detriment" with atezolizumab in PD-L1 negative (PD-L1–) patients, but there is also "no clear benefit."

He added, "In the PD-L1+ subgroup, we see a nearly 10-month overall survival difference, which I think is a key encouragement to see this drug as a new standard."

Nadia Harbeck, MD, PhD, head of the Breast Center at the University of Munich (LMU), Germany, who was not involved in the study, commented that, until now, the "tremendous effects" seen with immunotherapy in melanoma and lung cancer had not been replicated in breast cancer.

"We were sort of envying all the other diseases where immune therapy had played such an important role in the past," she said. "We hadn't seen that in breast cancer yet; the data so far were quite disappointing because only very few patients benefited."

Harbeck believes, however, that the current study "is something that will change practice in triple negative breast cancer."

Speaking to Medscape Medical News before the congress, Solange Peters, MD, PhD, chair, ESMO Scientific Committee, and Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, described the findings as a "complete revolution."

While she pointed out that, of all the subtypes of breast cancer, triple negative disease was always the most promising candidate for immunotherapy, she underlined that the idea that immunotherapy works in breast cancer "is a completely new paradigm."

Marleen Kok, MD, PhD, medical oncologist, the Netherlands Cancer Institute, Amsterdam, commented in an ESMO press release that although the benefit with atezolizumab in terms of PFS was "relatively small, around 3 months, the gain in overall survival in the PD-L1+ subgroup was impressive."

She believes that the results "will probably change the treatment landscape for our metastatic triple negative breast cancer patients," although she noted that it is not clear which is the best chemotherapy backbone.

Kok said that there are a number of ongoing anti-PD-L1 trials in breast cancer, which "should help answer the question of which chemotherapy backbone is most effective," but underlined the need for more studies to identify biomarkers that could help with patient selection.

Study Details

Accounting for only 15% of breast cancer cases, triple negative disease is also one of the most aggressive forms of the disease, with a median survival of no more than 18 months, and primarily affects younger women, Schmid explained.

As it does not respond to hormone therapy or drugs targeting HER2, first-line treatment typically consists of single-agent taxane or anthracycline chemotherapy, to which the majority of patients develop resistance within a few months.

Recently, studies have suggested that PD-L1 may be a suitable target in triple negative breast cancer, as the protein can inhibit anti-cancer immune responses and it is expressed on tumor-infiltrating immune cells in patients with the disease.

The researchers therefore undertook IMpassion130, enrolling patients with metastatic or inoperable locally advanced triple negative breast cancer who had only had prior chemotherapy in the curative setting.

All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

They were randomized to atezolizumab or placebo plus nab-paclitaxel in a double-blind fashion, with no crossover allowed, with treatment continued for at least six cycles in the absence of toxic effects.

During the press conference, Schmid explained that nab-paclitaxel was chosen because, at the time of designing the trial, "there was a big question mark whether the use of steroids could interfere with the activity of immunotherapy."

"In fact, there are data from other cancer subtypes where if you give higher doses of steroids it can impact on the immunotherapy response," he said.

"We know that paclitaxel and nab-paclitaxel have similar activity in metastatic triple negative breast cancer, but the difference is that nab-paclitaxel does not require the use of steroids, whereas as paclitaxel does require some use of steroids, at least initially."

Schmid said that, as this was the first trial of atezolizumab in this patient population, "we wanted to have the cleanest design and give it the best possible chance to establish whether immunotherapy adds to standard chemotherapy."

Patients underwent tumor imaging at baseline and every 8 weeks for 12 months, and then every 12 weeks. Follow-up for survival took place every 3 months after the discontinuation of treatment.

In all, 451 patients were randomized to each treatment, which included 185 patients in the atezolizumab group and 184 in the placebo group who were PD-L1+, defined as expression ≥ 1% on tumor-infiltrating immune cells.

The two treatment groups were well balanced in terms of baseline characteristics, and the PD-L1+ subgroup was generally representative of the overall intention-to-treat (ITT) population.

The median duration of atezolizumab and nab-paclitaxel treatment in the atezolizumab group was 24.1 weeks and 22.1 weeks, respectively, and the median duration of placebo and nab-paclitaxel in the placebo group was 22.1 weeks and 21.8 weeks, respectively.

After a median follow-up of 12.9 months, 358 (79.4%) of patients in the atezolizumab group and 378 (83.8%) of those in the placebo group had disease progression or died.

In the ITT population, median PFS was significantly longer with atezolizumab versus placebo, at 7.2 months versus 5.5 months, or a stratified hazard ratio of 0.80 (P = .0025).

The researchers calculated that the 1-year PFS rate was 24% with atezolizumab versus 18% with placebo.

When they looked specifically at the PD-L1+ population, they found that the median PFS was 7.5 months with atezolizumab versus 5.0 months with placebo, at a stratified hazard ratio of 0.62 (P < .0001).

The difference in 1-year PFS rate between atezolizumab and placebo was also greater in PD-L1+ patients, at 29% versus 18%.

The interim overall survival analysis in the ITT population did not reveal a significant difference between patients treated with atezolizumab versus those given placebo, at a stratified hazard ratio of 0.84 (P = .0840).

However, restricting the analysis to PD-L1+ patients revealed that atezolizumab appeared to be associated with a significant overall survival benefit versus placebo, at a stratified hazard ratio of 0.62.

In terms of toxicity, the two treatment groups were generally similar, with neutropenia, decreased neutrophil count, peripheral neuropathy, fatigue, and anemia the most common grade 3-4 adverse events in both groups.

Grade 3-4 peripheral neuropathy was, however, more common in the atezolizumab group than with placebo, seen in 6% versus 3% of patients. Atezolizumab patients were also more likely to experience a decreased neutrophil count, at 5% versus 3%.

At the press briefing, Schmid was asked whether he and his colleagues had expected to see a benefit with atezolizumab in all-comers, including PD-L1– patients.

"The short answer is we did," he said. "That's why we designed the trial the way it was, and that was based on several assumptions based on preclinical and clinical data."

He explained that chemotherapy can lead to downregulation of T-regulatory cells, "which are the negative regulators in the immune landscape," and can upregulate PD-L1.

They had also seen in the preceding phase 1b study that there was a benefit with atezolizumab in PD-L1– patients, and it is known that combination therapy can change the microenvironment of the tumor.

Schmid said, "So it's a long answer to say we had a clear rationale why the biomarker wouldn't be as binary as it seems to be and why there would be a benefit in PD-L1– patients, but the trial data are as they are and show a clear benefit in PD-L1+ patients but not in PD-L1– patients."

Speaking after the presentation of the data, invited discussant Giuseppe Curigliano, MD, PhD, from the Early Drug Development for Innovative Therapies Division at the University of Milan, Italy, said chemotherapy is known to potentially affect immunotherapy.

However, he asked whether paclitaxel is the "ideal partner" for atezolizumab in triple negative breast cancer, especially as many other chemotherapy agents have been shown to have immunogenic effects, some with a greater effect than that seen with paclitaxel.

He also pointed out that the researchers do not state how many patients in their study had BRCA mutations, which could have an impact on the outcomes because of their known effect on immunogenicity.

Curigliano said that to improve the results of IMpassion130 further, the patient population needs to be better selected for those who are likely to benefit from immunotherapy the most.

This means not just looking at PD-L1 expression, but also surrogates of immune response, tumor mutation burden, and microsatellite instability status, all of which have been observed to be altered in triple negative breast cancer patients.

In this way, it is already possible to identify patients who should and should not be considered for immunotherapy, he emphasized, which could lead to other novel therapeutic approaches that have not yet been fully tested.

This could include priming tumors with anticytotoxic T-lymphocyte-associated antigen 4 therapy, radiotherapy, or chemotherapy before starting patients on immunotherapy, or combining dual hormone receptor/HER2 blockade with immunotherapy.

Summarizing, Curigliano said that the field needs to work out how best to test tumors for PD-L1 expression and wondered if there was a "missing arm" from the study of atezolizumab alone.

He nevertheless echoed Schmid's conclusions that, with the current results, "we have a new standard of care in PD-L1+ triple negative breast cancer."

The study was funded by F. Hoffmann–La Roche/Genentech. Schmid has reported receiving honoraria from AstraZeneca, Bayer, Boehringer, Celgene, Eisai, Novartis, Pfizer, Puma, Roche/Genentech. He has received grants or been supported/had contracted research from Astellas, AstraZeneca, Medivation, Novartis, OncoGenex, Roche/Genentech (all paid to his institution). His wife is an employee of Roche. Disclosures for the other authors are listed in the article.

European Society for Medical Oncology (ESMO) 2018 Congress. Presented October 20, 2018. Abstract LBA1.

N Engl J Med. Published on October 20, 2018. Abstract

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