Immunotherapy plus chemo increases breast cancer survival rates

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Women with an aggressive type of breast cancer lived longer if they received immunotherapy plus chemotherapy, rather than chemo alone, a major study has found.  The New York Times reports that the results are expected to change the standard of care for women like those in the clinical trial, who had advanced cases of “triple-negative” breast cancer. That form of the disease often resists standard therapies, and survival rates are poor. It is twice as common in African-American women as in white women, and more likely to occur in younger women.

Researchers said the new study was a long-awaited breakthrough for immunotherapy in breast cancer. Until now, most progress had been in other cancers, including lung cancer and melanoma.

These findings may lead to the first approval by the US Food and Drug Administration for an immunotherapy drug to treat breast cancer. But the approval would likely be limited to a certain type of aggressive cancer.

Although triple-negative tumours occur in only about 15% of patients with invasive breast cancer in the US (or nearly 40,000 each year), they account for a disproportionate share of deaths, as many as 30% to 40%.

“These women really needed a break,” Dr Ingrid Mayer, a breast cancer specialist at Vanderbilt University, is quoted in the report as saying. “Nothing has worked well.” Mayer, who was not part of the study, called the findings “very significant.” She said she had received consulting fees from seven drug companies, including Genentech, which is the maker of the immunotherapy drug in the study and paid for the research.

The term triple-negative refers to the tumours’ lack of sensitivity to the hormones oestrogen and progesterone, and their lack of a protein called HER2, which is a target of treatment. The immunotherapy in the study was atezolizumab (brand name Tecentriq), which belongs to a class of drugs called checkpoint inhibitors; the chemotherapy was nab-paclitaxel (Abraxane).

The report says the findings were to be presented at a meeting of the European Society for Medical Oncology, in Munich. The study included 902 patients treated at 246 medical centres in 41 countries. Genentech, which is part of Roche, has already submitted the data to the FFA for approval.

Checkpoint inhibitors like atezolizumab work by helping T-cells – a type of white blood cell that is part of the immune system – recognise cancer and attack it. The drugs generally work for fewer than half of patients but can bring lasting recoveries even to people who were severely ill. Side effects can be dangerous, even life-threatening, and treatment costs more than $100,000 a year.

The report says in other cancers, researchers sometimes describe the tumours as “hot,” meaning they tend to have many mutations – genetic abnormalities that the immune system can recognise as foreign and attack.

But breast cancers tend to be relatively “cold,” with fewer mutations. The immune system is less likely to recognize them as invaders, which may help explain why previous studies of checkpoint inhibitors in breast cancer have been somewhat disappointing, researchers say.

In the new study, the report says the key to success seems to have been giving chemotherapy along with immunotherapy. “Chemo takes away the invisibility cloak the cancer has managed to put on,” Mayer said. The chemo may help to ignite the immune system, in part by killing cancer cells that then spill substances the T-cells detect as foreign and begin to hunt.

The new study “is a big deal and has been the buzz of the breast cancer research world,” said Dr Larry Norton of Memorial Sloan Kettering Cancer Centre. He was not involved in the study, although he said he had done paid consulting work for the past two years for the maker of Abraxane. Beyond changing treatment practices, he said the research “opens the door to new approaches to harness the immune system to fight breast cancer, and there is every reason to expect major advances there.”

He cautioned that the combined treatment would have to be studied further, to assess side effects.

Dr Kevin Kalinsky, a breast cancer specialist at New York-Presbyterian/Columbia University Irving Medical Centre, suggested in the report that patients like those in the study should talk to their doctors “about whether it is possible for them to get access to the medication while we’re waiting for FDA approval.” He did not take part in this study. He said he has received consulting fees from about 10 drug companies, including Genentech.

The women in the study had triple-negative breast cancer that had been newly diagnosed and had become metastatic, meaning it had begun to spread. Once that occurs, the outlook is grim, with many patients surviving 18 months or less. Half received chemo alone, and half were given chemo plus immunotherapy. Among those who received the combination, the median survival was 21.3 months, compared with 17.6 months for those who received chemo alone. The difference was not statistically significant.

But when the researchers looked at women who had a marker called PD-L1 on their cancer cells, the results were striking: The median survival was 25 months in the combination group, versus 15.5 months with just chemo. The report says that finding has not been analysed statistically, and the patients are still being followed.

Doctors say the survival difference is important. “This is truly a game changer,” said Dr Sylvia Adams, an author of the study from NYU Langone Health’s Perlmutter Cancer Centre.

Cancer patients with the PD-L1 marker tend to respond better to checkpoint inhibitors than those without it. In this study, 41% of patients had the marker. Genentech is seeking approval for treatment in triple-negative patients with the marker.

Adams said some patients, after initial treatment with both types of drug, have been doing well for two or three years with immunotherapy alone. The “million-dollar question,” she said, is whether they can safely stop the immunotherapy if they have no sign of cancer. For the time being, they are sticking with the treatment.

She noted that patients in the study had some of the expected side effects of immunotherapy, including lung and pancreas inflammation.

According to the report, Adams said she accepted no money from drug companies, but her medical centre did receive money from Genentech to pay for the research.

Abstract
Background: Unresectable locally advanced or metastatic triple-negative (hormone-receptor–negative and human epidermal growth factor receptor 2 [HER2]–negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)–paclitaxel may enhance the anticancer activity of atezolizumab.
Methods: In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1–positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1–positive subgroup).
Results: Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1–positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1–positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel.
Conclusions: Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1–positive subgroup. Adverse events were consistent with the known safety profiles of each agent

Authors
Peter Schmid, Sylvia Adams, Hope S Rugo, Andreas Schneeweiss, Carlos H Barrios, Hiroji Iwata, Eronique Diéras, Roberto Hegg, Seock-Ah Im, Gail Shaw Wright, Volkmar Henschel, Luciana Molinero, Stephen Y Chui, Roel Funke, Amreen Husain, Eric P Winer, Sherene Loi, Leisha A Emens

The New York Times report
New England Journal of Medicine abstract


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