No Survival Benefit With Immunotherapy in TN Breast Cancer

Liam Davenport

June 06, 2019

CHICAGO — Excitement over the interim results showing that immunotherapy improves progression-free survival (PFS) in triple negative breast cancer — which made headlines across the lay press last year — is now fizzing out somewhat. Second interim results from the IMpassion130 trial now show that there is no significant improvement in overall survival.

Patients with metastatic triple negative breast cancer considering immunotherapy with atezolizumab (Tecentriq, Genentech) should be counseled that the PFS benefit is modest and the impact on overall survival unclear, warned an expert discussing the results (abstract 1003) here at the American Society of Clinical Oncology (ASCO) 2019 annual meeting.

The study randomized patients with previously untreated locally advanced or metastatic triple negative breast cancer to atezolizumab or placebo plus nab-paclitaxel chemotherapy. Programmed death ligand 1 (PD-L1) status on immune cells was assessed using the Ventana PD-L1 (SP142) assay (Roche).

Interim study results were presented at the European Society for Medical Oncology 2018 Congress and simultaneously published in the New England Journal of Medicine.

They showed that atezolizumab was associated with a significant improvement in PFS, at 20% in the intention-to-treat analysis, rising to 38% among patients positive for PD-L1 expression.

This led to the US Food and Drug Administration (FDA) in March 2019 to grant the combination of atezolizumab and nab-paclitaxel accelerated approval for use in the treatment of metastatic triple negative breast cancer.

Further Results: Overall Survival 

The second interim results from the IMpassion130 study were presented here at the ASCO meeting by Peter Schmid, MD, PhD, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University, London, UK.

The study was conducted in patients with metastatic or inoperable local advanced triple negative disease who had not been previously treated.

They were randomized to intravenous atezolizumab 840 mg every 2 weeks or placebo, plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle, with no crossover permitted.

The study included 451 patients in each group, stratified by prior taxane use, presence of liver metastases, and PD-L1 status on immune cells; 41% of patients were PD-L1 positive in both treatment arms.

Schmid reminded the audience that, at the first interim analysis, the median PFS was 7.2 months in the atezolizumab group and 5.5 months in the placebo group, at a hazard ratio for progression of 0.80 (P = .002).

The difference was greater among PD-L1 positive patients, at a median PFS of 7.5 vs 5.0 months, or a hazard ratio of 0.62 (P < .001).

Now the second interim results show no significant overall survival benefit with atezolizumab versus placebo, either in the intention-to-treat analysis or in PD-L1-positive patients.

The median overall survival in the intention-to-treat population was 21.0 months in the atezolizumab group and 18.7 months in the placebo group, at a nonsignificant hazard ratio of 0.86 (P = .0777).

The 24-month overall survival rate was 42% with atezolizumab and 39% with placebo.

Schmid noted that the median overall survival with standard of care chemotherapy in metastatic triple negative breast cancer is approximately 18 months.

There was a numerical difference, however, in the subgroup of patients with higher PD-L1 expression.

Among PD-L1 positive individuals, the median overall survival was 25.0 months in those taking atezolizumab and 18.0 months for placebo, with a nonsignificant hazard ratio of 0.71.

The 24-month overall survival rate was 51% and 37%, respectively.

In the PD-L1 negative population, the median overall survival was 19.7 months in patients given atezolizumab and 19.6 months in the placebo group.

Schmid said that 61% of atezolizumab patients and 65% of those given placebo went on to receive another treatment, with 42% and 45%, respectively, receiving an antimetabolite such as gemcitabine and 27% in both groups receiving a platinum compound.

Patient-Reported Outcomes

Patient-reported outcomes from the study were also presented as a poster (abstract 1067) by Sylvia Adams, MD, New York University Cancer Institute, New York City, and colleagues.

In this analysis, patients completed the EORTC QLQ-C30 and breast cancer module at the start of each treatment cycle, at the end of treatment, and every 4 weeks for a year.

Time to deterioration, defined as the first decrease in scores from baseline of at least 10 points, was comparable in the two treatment groups, at a hazard ratio for atezolizumab versus placebo of 0.97 in the intention-to-treat analysis and 0.94 in PD-L1 positive patients.

The time to deterioration of physical function and role function were also similar between atezolizumab and placebo in both the intention-to-treat population and PD-L1 positive patients.

Moreover, Adams and colleagues found that health-related quality of life, physical and role function, and treatment symptoms such as fatigue, diarrhea, nausea and vomiting were stable, with no clinically meaningful changes until discontinuation.

First to Show Benefit — But Benefit Is Modest

Summarizing the results, Schmid said that IMpassion130 is the "first and only phase 3 study to show a clinically meaningful benefit of first-line immunotherapy in metastatic triple negative breast cancer."

He added that the use of the SP142 assay to measure PD-L1 expression on immune cells "predicts clinical benefit with atezolizumab and nab-paclitaxel."

Noting the late safety signals, Schmid said the combination "sets a new benchmark as the first therapy to cross the 2-year landmark overall survival benefit in patients with PD-L1-positive metastatic triple negative breast cancer."

However, study discussant Cesar Augusto Santa-Maria, MD, Northwestern University Feinberg School of Medicine, Chicago, Illinois, was more circumspect.

He noted that the drug combination achieved a "modest improvement in PFS in the intention-to-treat population; a little more so in the PD-L1 positive subgroup." And he pointed out that the overall survival benefit was not statistically significant.

He also pointed out that the accelerated approval given by the FDA did not specify at what point in the disease trajectory atezolizumab should be used, and the accelerated approval is "contingent on future studies."

Santa-Maria also said that the use of atezolizumab plus nab-paclitaxel in IMpassion130 was in-line with other studies, the findings of which suggest that "most of the responses are limited to the front-line setting."

"Another point I'd like to make is the challenge of assessing PD-L1 status in immune cells and some of the issues with the SP142 assay," he continued.

He said that in lung cancer the SP142 assay is less sensitive than other PD-L1 assays, in both immune cells and tumor cells, and "there are some issues with concordance when multiple pathologists evaluate immune cell PD-L1 testing," which is a problem that applies to all assays.

For clinical practice, Santa-Maria said that SP142 should be the "preferred assay for now, but certainly optimization and validation is critical here and is going to take a joint effort to do so."

Overall, he believes that it is "certainly reasonable" to consider atezolizumab plus nab-paclitaxel in triple negative breast cancer and it should be used "mostly in the front-line setting...with very rare situations where you may consider it in further lines."

Santa-Maria added it is important that patients be counseled on the modest progression-free survival benefits and the undefined overall survival benefit.

The study was sponsored by Hoffmann-La Roche. Schmid has disclosed financial relationships with AstraZeneca, Novartis, Pfizer, Roche, Bayer, Boehringer Ingelheim, Celgene, Eisai, Genentech, Merck, Puma Biotechnology, Astellas Pharma, Medivation, and Oncogenex. Adams has disclosed financial relationships with BMS, Genentech, GlaxoSmithKline, Merck, Amgen, Celgene, and Novartis. Other researchers have also disclosed financial relationships. Santa-Maria has disclosed financial relationships with Genomic Health, Halozyme, Polyphor, Medimmune, Pfizer, and Tesaro.

ASCO 2019. Presented June 2 (abstract 1067) and June 4, 2019 (abstract 1003)

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