1. Goodwin, Peter M.

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COPENHAGEN, Denmark-Progression-free survival (PFS) was significantly prolonged-with a higher rate of myelosuppression-among postmenopausal women who had HR-positive, HER2-negative advanced breast cancer who received first-line treatment with ribociclib added to their letrozole endocrine therapy in findings reported at the European Society for Medical Oncology 2016 Congress (N Engl J Med 2016; DOI: 10.1056/NEJMoa1609709).

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"After 15.3 months of median follow-up, interim analysis showed a dramatic difference between the two arms of the study," said Gabriel Hortobagyi, MD, FACP, Professor of Medicine at the University of Texas MD Anderson Cancer Center's Department of Breast Medical Oncology in Houston.


The double-blind randomized phase III Mammary Oncology Assessment of LEE011 (ribociclib) Efficacy and Safety (MONALEESA-2) trial, divided 668 patients evenly between those in the control group receiving endocrine therapy with the aromatase inhibitor letrozole plus placebo and those in the experimental arm who were treated with letrozole plus ribociclib-a drug that inhibits cyclin-dependent kinases 4 and 6 (CDK 4/6), which are key mediators of endocrine resistance. Patients had no prior treatment in the metastatic setting and were treated daily until progression.


In patients treated with the ribociclib combination median duration of PFS ranged from 19.3 months (95% confidence interval) to "not reached" as compared with 14.7 (ranging from 13.0 to 16.5) months in the control group. The hazard ratio was estimated as 0.56 and was highly significant (p = 0.00000329). After 18 months, 63 percent were free of disease as compared with 42 percent of patients treated with letrozole plus placebo.


The study also found that patients who had both ribociclib and letrozole had significantly higher rates of overall response and clinical benefit than with letrozole plus placebo. Longer PFS was found in all sub-groups of patients including a high proportion who were probably already sensitive to endocrine therapy-suggesting the CDK 4/6 blocker could have a role beyond reversing endocrine resistance.


Hortobagyi said that documenting the final impact on PFS and assessing overall survival would "probably need another year or two, perhaps longer." But he described the interim findings as "a very powerful demonstration of difference," and he expected that practice would change.



The large positive increments in survival were achieved with relatively little additional toxicity, he said, noting that, although ribociclib increased side effects slightly, these were mostly asymptomatic. "The most common side effects are hematologic such as leukopenia, neutropenia, anemia, and thrombocytopenia," Hortobagyi told Oncology Times, and he said less than 10 percent were symptomatic or grade 4.


"Neutropenic fever, for instance, occurs in less than 1.5 percent of patients," he said. Symptomatic side effects such as nausea, vomiting, alopecia, and diarrhea were less common than hematologic toxicities and were mostly grade 1 or 2. "And they can be very effectively managed with dose interruptions or in some cases dose reductions," he explained.


Stephen R.D. Johnston, MD, PhD, MA, FRCP, Professor of Breast Cancer Medicine at the Royal Marsden Hospital and Institute of Cancer Research in London, described the improvement of PFS between the two arms as "very impressive" and he said the hazard ratio of 0.56 was a "very significant improvement in benefit and efficacy."


He pointed out that the early separation of the PFS curves implied that patients were benefiting from the targeted combination whether their disease was endocrine-resistant or still endocrine-sensitive. "The efficacy and toxicity data are very clear," he said, noting there was a significant improvement in PFS, response rate, and clinical benefit rate and "the benefit was seen across all sub-groups and toxicity was predictable and manageable."


Johnston compared the MONALEESA-2 findings with similarly positive results from the PALOMA-2 study-reported only a few months previously-using another CDK 4/6 inhibitor, palbociclib. He embraced the concept of using first-line targeted therapy in hormone-sensitive metastatic breast cancer and welcomed the contribution MONALEESA-2 had made.


"Because we now have two randomized studies in similar populations-within 4 months of each other-that show substantial improvement in progression-free survival, I think that meets the criterion [as] level one evidence of being a game changer," he said.


Hortobagyi said the addition of ribociclib to letrozole "probably reverses or prevents the development of endocrine resistance, at least for some time." He noted that, upon appropriate regulatory acceptance, ribociclib should become "one of the leading options for treating metastatic breast cancer in previously untreated women with HR-positive breast cancer," and he thought this was appropriate "because of the magnitude of benefit and the benefit/risk ratio of this agent."


Hortobagyi also held out a vision for the future if the MONALEESA-2 benefits can be replicated in the adjuvant setting for early breast cancer. "We hope that this combination can be tested in primary breast cancer where it would reach hundreds of thousands of women around the world," he said.


Commenting on the findings, Giuseppe Curigliano, MD, PhD, Director of the New Drugs and Early Drug Development for Innovative Therapies Division at the European Institute of Oncology, Milan, Italy, said, "I believe the results of this study are significant because now we have a new CDK4/6 inhibitor for patients with estrogen-receptor positive metastatic breast cancer, in addition to palbociclib (already FDA-approved) and abemaciclib (under development).


"The addition of ribociclib to letrozole does increase the rate of toxicity; but overall, if we evaluate the magnitude of clinical benefit, there is definitely a benefit to be gained from adding ribociclib," he said, adding that further studies of ribociclib should examine the use of cancer biomarkers to better identify patients who would respond to the combination.


Peter M. Goodwin is a contributing writer.