Are Targeted Therapies Ready for 'Big Time' in ER-Positive Breast Cancer?

Liam Davenport

October 10, 2016

COPENHAGEN — Should a targeted therapy be added to endocrine therapy in the treatment of hormone-dependent metastatic breast cancer? Should such a combination now be standard of care? These questions were debated here at the European Society for Medical Oncology (ESMO) Congress 2016.

Opening the session, Michael Gnant, MD, director at the Department of Surgery, Vienna Medical University, Austria, said, "We've seen exciting data at this meeting, and previously, about advances in the treatment of ER [endocrine receptor]-positive breast cancer, and the controversy about it is going to go on."

He was referring to new data presented here for the investigational cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor ribociclib (Novartis) with letrozole, as well as published data for palbociclib (Ibrance, Pfizer), in the treatment of ER-positive metastatic breast cancer. As previously reported by Medscape Medical News, experts here said that the new data are leading to a "paradigm shift" in the management of this disease.

But clinicians in the audience did not appear to be convinced.

The question for the debate was whether combined endocrine therapy with targeted agents should now be the standard of care for ER-positive metastatic breast cancer.

Clinicians in the audience were invited to cast their votes on six debate questions on different therapeutic scenarios (see below). Round 1 votes were cast before the debate began, and round 2 votes were cast after the debate.

Combination Superior to Single Agent

The "yes" argument to support the motion that combined endocrine therapy with targeted agents should now be the standard of care for ER-positive metastatic breast cancer was outlined by Angelo di Leo, MD, PhD, head of the Medical Oncology Unit, Department of Oncology, Hospital of Prato, Istituto Toscani Tumori, Prato, Italy.

Dr di Leo said that the PALOMA 2 trial, which compared palbociclib and placebo in combination with letrozole; the PALOMA 3 trial, which compared palbociclib and placebo in the context of fulvestrant therapy; and the BOLERO 2 trial, which looked at everolimus or placebo with exemestane had changed practice in the treatment of ER-positive/human epidermal growth factor receptor (HER)-2–negative advanced breast cancer.

He said that the MONALEESA-2 trial, presented here at ESMO 2016, can now be added to this list. As reported by Medscape Medical News, this trial showed that adding the investigational CDK4/6 inhibitor ribociclib to letrozole showed a significant improvement in progression-free survival when compared with letrozole alone.

"Whatever the setting, whether first-line, second-line or third-line, the results of these important studies are clearly showing that combination therapy is better than single agent," he said.

Dr di Leo noted that most patients in these trials had previously benefited from a prior round of endocrine therapy, while the remainder were endocrine therapy naive. Before the latest results with combination therapy, it was assumed that they would receive endocrine therapy alone. However, combination therapy has been shown to be "better."

Specifically, progression-free survival (PFS) is improved with the treatments in the trials compared with placebo, and subgroup analysis has shown that there is "not one single" subgroup in which a single agent is better than combination therapy.

However, Dr di Leo said, because the PFS curves show that many patients experience relapse, particularly in the first 6 months of treatment, predictive markers are required to identify these patients and potentially allow them to be treated in a different way.

Further considerations, he noted, are the safety profile of the combination therapy, the overall survival benefit, and the "financial" toxicity.

In terms of safety, he pointed out that no combination therapy is less toxic than a single agent. However, the safety impact of the current combinations is not serious because most adverse effects were grade 1.

Dr di Leo acknowledged the lack of overall survival data: The data from the PALOMA and MONALEESA studies are not yet mature, and BOLERO 2 showed no survival benefit.

He countered, however, that the trials were not powered to detect overall survival differences. Furthermore, overall survival is not a sensitive endpoint because its determination is often confounded by noninvestigational therapies being given after disease progression in trials and by crossovers between study groups.

The financial impact of the drugs is substantial, Dr di Leo conceded. However, he argued that health economy assessments "must not be the primary aim of treating physicians" and that the "main responsibility" of a physician is to use the latest treatments "according to the principles of evidence-based medicine."

High Relapse Rate

Arguing on the "no" side of the debate, Jonas Bergh, MD, PhD, professor, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden, argued that the initially high rate of relapse after initiation of combination therapy in the trials highlighted by Dr di Leo as requiring predictive markers can be readily explained. Pointing to a 2012 paper by Lindström et al, he said that clinically used breast cancer markers, such as estrogen receptor and HER2 status, are unstable throughout tumor progression.

Dr Bergh noted that the currently available guidelines for the treatment of breast cancer show a "great deal of uncertainty" regarding whether to recommend combination therapy in ER-positive breast cancer. He added: "There's a bit of 'concern,' 'could be considered,' 'may,' et cetera, so I think this is may be a slightly more reflective view on this complicated issue."

He also pointed out that there are no data on whether the drugs should indeed be used in combination or rather in sequence, "and the reason for that is, of course, that there are theoretical concerns but there are also concerns over harming the patient."

Dr Bergh agreed with Dr di Leo that the lack of an observed survival benefit with combination therapy could indeed be due to crossover or a lack of follow-up, "but the worst scenario is that these targets are not good enough" and the current data are "a little bit problematic."

Summarizing, he said that he cannot support the notion that combined endocrine therapy with targeted agents should now be the standard of care for ER-positive metastatic breast cancer because there have, so far, not been any survival gains and, in some cases, the side effects have been "quite challenging."

He said that chemotherapy should also be considered in these patients if indicated, although no prospective data currently support this. The financial impact is also of concern, particularly considering uptake and usage in different regions and countries.

Audience Responses

The audience then voted again on the same questions as before.

The second round of voting showed that the audience felt that not all patients with ER-positive metastatic breast cancer should receive first-line combination therapy, that patients with limited disease can receive endocrine therapy alone, and that the newer targeted agents postpone the use of chemotherapy. Most audience members agreed that cost could be an issue in preventing the widespread use of these agents.

The audience was largely split as to whether the overall survival data should be a factor in deciding whether to use targeted agents in ER-positive metastatic breast cancer. However, they were more certain that chemotherapy should not be used upfront as an indiction therapy.

Dr Gnant commented that the debate did not substantially change audience opinions, although it did reduce the number of "don't know" responses and did strengthen some opinions. The audience was more persuaded, however, that cost should not be an issue in preventing the adoption of newer, targeted therapies.

Questions

  1. Should all patients with ER-positive metastatic breast cancer receive first-line CDK4/6 inhibitors or mammalian target of rapamycin (mTOR) inhibitors together with endocrine therapy?

  2. Can patients with limited disease (eg, single bone lesion) receive endocrine therapy as first-line treatment?

  3. Is lack of overall survival data a key limitation in the use of targeted agents in ER-positive metastatic breast cancer?

  4. Is cost an issue that should prevent a widespread use of these new agents?

  5. Does the arrival of targeted agents postpone the use of chemotherapy in ER-positive metastatic breast cancer?

  6. Should chemotherapies rather be used upfront, as induction, when patients usually can better tolerate side effects than in later lines, when they have progressed and likely tolerate these therapies less well?

Table. Audience Responses (Percentage) before (Round 1) and After (Round 2) the Debate

Question Yes: Round 1 Yes: Round 2 No: Round 1 No: Round 2 Don't Know: Round 1 Don't Know: Round 2
1 21.3 22.7 69.5 74.9 9.2 2.3
2 86.0 83.2 11.7 15.3 2.3 1.5
3 41.8 41.1 50.8 56.9 7.3 2.0
4 71.8 65.7 23.7 31.9 4.6 2.4
5 79.9 70.4 14 23.5 6.1 6.1
6 24.1 25.5 69.2 70.5 6.7 4.0

No funding reported. Dr di Leo reports acting in an advisory role for AstraZeneca, Bayer, Celgene, Lilly, Novartis, Pfizer, and Roche and receiving lecture fees from AstraZeneca, Eisai, Genomic Health, Novartis, Pfizer, Pierre Fabre, and Roche.

European Society for Medical Oncology (ESMO) Congress 2016. "Should Combined Endocrine Therapy With Targeted Agents Now Be the Standard of Care for ER+ Metastatic Breast Cancer?" Presented October 8, 2016.

Follow Medscape Oncology on Twitter: @MedscapeOnc

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