CDK4/6 inhibitors change landscape of breast cancer treatment: 2 studies

New data from 2 studies has shown that treatment with a CDK4/6 inhibitor plus fulvestrant improves overall survival in women with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer [1,2].

The 2 studies included different patient populations as well as different CDK4/6 inhibitors used in different lines of therapy: Monarch 2 evaluated abemaciclib plus fulvestrant in patients with advanced breast cancer after failure of endocrine therapy and regardless the menopausal status; the Monaleesa-3 study investigated ribociclib plus fulvestrant as first- or second-line combination therapy only in postmenopausal patients.

Results of the Monaleesa-3 [1] trial have shown that first-line as well as second-line treatment with the CDK4/6 inhibitor ribociclib plus fulvestrant significantly improves overall survival in postmenopausal patients with HR+, HER2- advanced breast cancer. The benefits with ribociclib plus fulvestrant were seen in women not previously treated with hormonal therapy as well as in those who had become resistant to endocrine therapy.

"This is a significant, practice-changing report, in that we are now saying that patients with advanced breast cancer will have an overall survival benefit if they get the CDK4/6 inhibitor ribociclib upfront at the time of their recurrence, even if they have not had any prior endocrine therapy at the time of presenting with metastatic disease,” said presenting author Prof. Dennis Slamon (University of California Los Angeles, USA).

"The argument has always been by some experts that you should first treat with endocrine therapy alone and then if patients recur, you would add something like a CDK4/6 inhibitor. In other words, you get what you can out of endocrine therapy alone, and save a CDK4/6 inhibitor until the subsequent recurrence. The data from Monaleesa-3 clearly show that if postmenopausal patients receive this right up front there is a very significant benefit, not only in progression-free survival –which had already been published– but now with this new report in overall survival, which is the hardest endpoint to reach and the most important one in terms of making an impact on the disease,” Prof. Slamon explained.

The same session featured another trial, Monarch 2, which showed statistically and clinically meaningful improvement in overall survival with the CDK4/6 inhibitor abemaciclib plus fulvestrant in pre- and peri- as well as in postmenopausal women with HR+, HER2- advanced breast cancer resistant to hormonal therapy [2].

"Results from the Monarch 2 study presented two years ago [3] showed significant improvement in progression-free survival for patients treated with the combination of abemaciclib plus fulvestrant compared with fulvestrant alone. Now, with further follow-up we have overall survival data showing a statistically significant and clinically meaningful improvement in overall survival with the combination,” said study first author Prof. George Sledge (Stanford University School of Medicine, USA).

Prof. Nadia Harbeck (University of Munich, Germany) commented on the relevance of the new studies, “The results of Monarch 2 nicely complement those reported in Monaleesa-3. Abemaciclib is the third CDK4/6 inhibitor to show an overall survival benefit in advanced HR+, HER2- breast cancer. Together with the data we have seen before with palbociclib [4] and ribociclib, these new data strengthen the argument that we should start treatment in the metastatic setting with a CDK4/6 inhibitor plus endocrine therapy because these drugs substantially improve patient outcomes compared with anti-hormonal treatment alone.”

Considering possible limitations of the studies, Prof. Harbeck said, “All three of the CDK4/6 inhibitors powered their studies for progression-free survival and not for overall survival. Nevertheless, I think the data are strong enough, taken together, to give us certainty that this is really the way forward in this disease; to go for endocrine-based therapy plus CDK4/6 inhibition and not just endocrine therapy alone.” She added that she would like to see detailed quality of life data from Monarch 2 to accompany the survival data and hoped this will be made available in the future. Moreover, she stated that these results make the doctors and patients hopeful for the results of the CDK4/6 inhibitor studies in early breast cancer, the first ones of which will be reported in the near future.

1. Slamon D et al. Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer (ABC) treated with fulvestrant (FUL) + ribociclib (rib). ESMO Congress 2019, 27 Sept-1 October 2019, Barcelona, Catalonia, Spain, Abstract LBA7_PR.
2. Sledge GW et al. Monarch 2: overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer. ESMO Congress 2019, 27 Sept-1 October 2019, Barcelona, Catalonia, Spain, Abstract LBA6_PR.
3. Sledge GW et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced cancer who had progressed while receiving endocrine therapy. JCO 2017; 35: 2875-2884
4. Turner N et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med 2018; 379:1926-1936. DOI: 10.1056/NEJMoa1810527

Posted on 26 November 201929 February 2024