ASCO 2017-CDK 4/6 INHIBITORS IN BREAST CANCER

There have been a number of interesting breast cancer presentations at the American Society of Clinical Oncology (ASCO) annual meeting this year, including several reports of CDK 4/6 inhibitors in patients with hormone receptor–positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) presented on Saturday, June 3.

To reiterate the landscape up until this point, there are currently two FDA-approved CDK 4/6 inhibitors in HR+/HER2- MBC: palbociclib and ribociclib. Prior to ASCO 2017, we knew that palbociclib received conditional approval in February 2015, based on a randomized, open-label phase 2 trial with front-line letrozole with or without palbociclib (PALOMA-1 trial). Subsequent randomized, placebo-controlled, phase 3 trials have demonstrated a significant benefit in progression-free survival (PFS) with front-line letrozole (PALOMA-2 trial) or with fulvestrant after prior progression on anti-estrogen therapy (PALOMA-3 trial). More recently, ribociclib was approved in March 2017 on the basis of the randomized phase 3 MONALEESA-2 trial of front-line letrozole with or without ribociclib.

So, what did we learn in Saturday's session at ASCO?

Updates on Abemaciclib

We saw the first presentation of a randomized, phase 3 abemaciclib trial.^[1]MONARCH 2 was a double-blind, placebo-controlled trial of fulvestrant with or without abemaciclib in women with HR+/HER2- MBC who had progressed while receiving endocrine therapy. (It was also a rapid communication published in Journal of Clinical Oncology .)Endocrine-resistant disease included those who relapsed on neoadjuvant or adjuvant therapy within 1 year or who progressed on first-line endocrine therapy. Median follow-up was 19.5 months. There was a significant improvement in PFS—the primary endpoint—from 9.3 months with fulvestrant alone to 16.4 months with the combination (hazard ratio, 0.55). The forest plot showed all subgroups favoring the combination.

Of note, the side-effect profile of abemaciclib is different from that of palbociclib and ribociclib. Neutropenia rates are relatively lower (total 46%, grade 3: 23.6%). Gastrointestinal side effects are higher, including diarrhea (total 86.4%, grade 3: 13.4%). Other notable aspects of this presentation: This is a different population from PALOMA-3's, including that no prior chemotherapy was allowed in MONARCH-2, potentially helping to explain the numerically longer PFS with the control arm in MONARCH-2 than previously observed in other studies, such as PALOMA-3. Also, there was a required dose reduction for all patients in the trial from 200 mg twice daily to 150 mg twice daily, which was better tolerated.

These data, plus the MONARCH-1 data presented last year at ASCO and recently published, are compelling. In addition, MONARCH-3, another phase 3 trial with front-line letrozole with or without abemaciclib, has been reported in press releases as positive for the combination. Stay tuned for these data in the future, as well as for potential approval for abemaciclib in MBC.

Is There an Overall Survival Advantage for CDK 4/6 Inhibitors?

Maybe. The updated results of PALOMA-1^[2] were presented today. With a median follow-up of 65 months, there was a numerical trend toward improvement with the combination (37.5 months vs 34.5 months)but it was not statistically significant. However, this study was not powered to look at overall survival. We will await future updates of studies like PALOMA-2 and MONALEESA-2 to answer this question. One other notable finding: the median time to chemotherapy initiation of 26.7 versus 17.7 months with the combination and single-agent letrozole, respectively (HR, 0.66).

Is There a Benefit of CDK 4/6 Inhibition in a Moderately Pretreated Population?

Yes. The TREnd trial was a two-stage, noncomparative, randomized, phase 2 trial.^[3]I Patients with one or two prior lines of endocrine therapy were randomly assigned to palbociclib or palbociclib plus the endocrine therapy that they recently received. Both arms demonstrated activity as demonstrated by a predefined clinical benefit rate of > 40%. In an exploratory analysis, the duration of clinical benefit (11.5 months vs 6 months) and PFS (10.8 months vs 6.5 months) were numerically higher in those who received endocrine therapy plus palbociclib as opposed to palbociclib alone.

As you can see, that's a lot of data. However, there are important questions to answer in the future, including:

• Can we identify which patients will benefit with endocrine therapy alone, given the associated cost and potential side effects of CDK 4/6 inhibitors?
• Is there a role for sequencing CDK 4/6 inhibitors in the metastatic setting?
• Will we identify markers of response/resistance to CDK 4/6 inhibitors, and markers that will demonstrate benefit with one agent over another?
• What will be the benefit with these drugs in the adjuvant setting?

Studies attempting to answer these questions are ongoing. But hearing the session at ASCO 2017, one cannot argue that this drug class remains an important step forward in the treatment of HR+/HER2- MBC.