AE Risks With Combined Tx for Advanced Breast CA

Kristin Jenkins

November 08, 2017

LISBON, Portugal — For  women already taking endocrine therapy for breast cancer, adding targeted agents can significantly increase overall risk for grade 3 or 4 adverse events (AEs), say researchers.

These targeted agents include cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and anti–human epidermal growth factor receptor 2 (HER2) drugs.

Until now, conflicting evidence about the efficacy and toxicity of endocrine therapy plus targeted agents has presented clinicians with a decision-making challenge, commented Matteo Lambertini, MD, from the Institut Jules Bordet and the Université Libre de Bruxelles, Belgium.

New results from a meta-analysis of 16 randomized controlled trials show that the AE risk varies by class of drug. It also shows that side effects, such as neutropenia, stomatitis, hyperglycemia, fatigue, and diarrhea, can be managed early in the course of treatment to minimize negative effects on quality of life, he said.

These results may improve clinicians' understanding of the potential toxicities associated with combination therapy and help them choose the best course of treatment and how to counsel patients, he commented.

Dr Lambertini was speaking here at the Advanced Breast Cancer Fourth International Consensus Conference. The results were also published online November 3 in Cancer Treatment Reviews .

The meta-analysis found that the addition of CDK4/6 inhibitors to hormone therapy almost tripled the risk for grade 3 or 4 AEs, while adding anti-HER2 agents increased the AE risk 2.5-fold. The risk for grade 3 or 4 AEs doubled when P13K inhibitors or mTOR inhibitors were part of combination therapy.

In addition, certain AEs were also associated with some targeted agents but not with others. For instance, the risk for grade 3 or 4 fatigue was greatly increased with the use of anti-HER2 agents, CDK4/6, and PI3K inhibitors but not with mTOR inhibitors. Similarly, there was an increased risk for grade 3 or 4 diarrhea with anti-HER2 agents, PI3K, and mTOR inhibitors but not with CDK4/6 inhibitors.

Despite this, most patients with advanced hormone receptor–positive breast cancer "are candidates to receive a combined treatment with targeted agents and hormone therapy at some point," Dr Lambertini emphasized.

"Survival data are still immature for several studies involving targeted therapies, especially for CDK4/6 inhibitors," he told Medscape Medical News. "Despite potential toxicities associated with their use, these agents should be considered in patients with hormone receptor–positive/HER2-negative metastatic breast cancer as side effects can sometimes have only a limited impact on the patient's quality of life."

In a statement, conference chair, Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Centre, Lisbon, pointed out that of the four targeted agents included in the analysis, only anti-HER2 therapies have been shown to improve patient survival.

"This study clearly highlights that combined treatment with endocrine therapy and targeted agents is substantially more toxic than endocrine therapy alone," said Dr Cardoso. "Therefore, the benefit provided must be balanced with their added toxicity, and some patients will be very well treated with endocrine therapy alone."

When approached for comment, Eric P. Winer, MD, professor of medicine at Harvard Medical School and director of the breast oncology center at Dana-Farber Cancer Institute, Boston, Massachusetts, agreed. "One has to be a bit cautious in interpreting this [study]," he said.

"When you're making treatment decisions for patients with advanced cancer, it's one thing if there's a survival benefit. But if there's no survival benefit, you have to weigh the side effects and how the patient perceives them," he told Medscape Medical News.

The fact that the investigators of the current study report more toxicity with the addition of targeted therapy comes as no surprise, he added.

"This has to be balanced against the potential benefits of these drugs. In some cases, they are somewhat beneficial, adding months of progression-free survival but not much more than that," he said.

When it comes to quality of life, however, that's another matter, Dr Winer emphasized. "It's about the details, and how much these adverse effects affected quality of life."

Most of the AEs had a profound effect on quality of life, with the exception of grade 3 neutropenia seen with CDK4 inhibitors. This can be effectively managed without a huge impact on quality of life, he pointed out. But there is also another side to this, he noted, referring to recent data from a phase 3 clinical trial with the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer): "Here's the catch: palbociclib may actually improve quality of life," he said.

Details of Meta-analysis

For their meta-analysis, Dr Lambertini and colleagues analyzed data from 16 randomized clinical trials with a total of 8529 participants diagnosed with hormone receptor–positive metastatic breast cancer. Of these, 1995 were also diagnosed with HER2-positive disease.

Participants had been randomly assigned to treatment with hormone therapy alone or in combination with CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, and anti-HER2 agents up to March 31, 2017.

Hormone therapy included the following:

  • Tamoxifen, a selective estrogen receptor modulator;

  • Aromatase inhibitors letrozole (Femara, Novartis), anastrozole (Arimidex, AstraZeneca), and exemestane (Aromasin; Pfizer); and

  • Fulvestrant (Faslodex, AstraZeneca), a selective estrogen receptor degrader.

Although the addition of targeted agents to endocrine therapy was associated with a significantly higher risk for grade 3 or 4 AEs overall, different agents were associated with different degrees of risk.  The investigators identified specific side effects for each drug and then calculated AE summary risk estimates by drug class as odds ratios (ORs) and 95% confidence intervals.

The greatest risk for grade 3 or 4 neutropenia (OR, 40.77) was seen with CDK4/6 inhibitors palbociclib (Ibrance), ribociclib (Kisqali, Novartis), and abemaciclib (Verzenio, Lilly). However, clinical experience has shown that CDK4/6 inhibitors are better tolerated than mTOR or PI3K inhibitors, noted Dr Lambertini. In addition, AEs associated with the use of CDK4/6 inhibitors "can be managed relatively easily with early detection and dose delay or reduction, if necessary," he said.

The greatest risk for grade 3 or 4 hyperglycemia (OR, 40.93) was seen with PI3K inhibitors buparlisib (BKM120, Novartis AG) and pictilisib (GDC0941, Roche), while risk for grade 3 or 4 diarrhea (OR, 9.93) was greatest with anti-HER2 agents trastuzumab (Herceptin, Roche/Genentech) and lapatinib (Tyverb, Novartis).

The largest risk for grade 3 or 4 stomatitis was seen with the addition of mTOR inhibitors everolimus (Afinitor, Novartis) and temsirolimus (Torisel, Wyeth Pharmaceuticals).

Recently, an alcohol-free dexamethasone mouthwash has been shown to reduce the incidence and severity of sore and inflamed tissues in the mouth in patients treated with everolimus and exemestane, pointed out Dr Lambertini. "It is likely to be considered as a new standard of care."

The findings also "highlight  the importance of incorporating patient-reported outcomes in oncology trials" because they more accurately measure "the actual frequency, severity, and real impact of anticancer treatment on patients' quality of life," said Dr Lambertini. This was not done in the current study, he noted.

Dr Lambertini reports relationships with Teva and Astellas. Study coauthor Evandro de Azambuja, MD, PhD, reports relationships with Roche and GlaxoSmithKline. Dr Winer reports relationships with Genentech and Lilly. No other relevant financial relationships have been disclosed.

Advanced Breast Cancer Fourth International Consensus Conference (ABC 4). Abstract BP66. Presented November 3, 2017.

Cancer Treat Rev. Published online November 3, 2017. Abstract

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