PALOMA-1 confirms expectations, but will it support regulatory filing?

Final progression-free survival (PFS) data from the PALOMA-1 phase II trial was presented at the Plenary Session of the 2014 American Association for Cancer Research (AACR; Finn, abstract CT-101). Observers were expecting positive news, since interim analyses already had shown PFS benefit for palbociclib (PD 0332991, Pfizer/Amgen/Onyx) and Pfizer had indicated via press release that the final PFS results were positive (February 3, 2014). However, the big question wasn’t whether the data would be positive, it was whether the final data would be good enough to support filing for accelerated approval.

PALOMA-1 (NCT00721409) was an open label trial that randomized 165 patients to letrozole or letrozole plus palbociclib. As part of the trial design, both CCND-1 amplification or p16 loss were prospectively evaluated as biomarkers, but only ER-status was predictive of activity (Finn, Abstract 100O, IMPAKT 2012). An interim analysis based on 61 events presented at the San Antonio Breast Cancer Symposium (SABCS) in 2012 demonstrated a striking 18.6 month improvement in PFS when palbociclib was added to letrozole  (26.1 months versus 7.5 months, HR 0.37, p<0.001; Finn, Abstract S1-6).

The final analysis consisted of 100 PFS events, and palbociclib maintained the impressive PFS benefit (20.2 months versus 10.2 months, HR 0.488, p=0.0004). All evaluated subgroups showed a strong benefit for palbociclib. Palbociclib plus letrozole also increased objective response rate (ORR; 43% versus 33%; primarily partial responses) and clinical benefit rate (81% versus 56%). The presenter suggested that the lower response rate could be attributed to fact that PALOMA-1 included patients with bone metastases that cannot be easily assessed for response. Further efficacy analysis conducted in patients with measurable disease (n=65 in palbociclib arm and n=66 in letrozole arm) demonstrated an ORR of 55% versus 39%.  Preliminary analysis on overall survival (OS) indicates only a trend to an OS benefit: 37.5 months versus 33.3 months, HR 0.813, 0.2105). The toxicity profile for palbociclib was manageable given that the relative dose intensity was 94% and the discontinuation rate due to adverse events (AEs) was 13% in palbociclib plus letrozole versus 2% in letrozole alone arm. Common Grade 3/4 toxicities in palbociclib plus letrozole versus letrozole alone arm included neutropenia (54% versus 1%), leucopenia (19% versus 0%), fatigue (4% versus 1%) and anemia (6% versus 1%).

The impressive PFS benefit was definitely well received by those in attendance at the conference. The discussant (Dr. Jose Baselga) stated “these results are strikingly positive and with a large potential impact to patients with ER+ breast cancer.” The important question remains: what will Pfizer do with these data? Palbociclib was awarded “breakthrough therapy” designation in April 2013 based on the interim data from PALOMA-1. Moreover, historical data presented by Dr. Finn suggest that the PFS benefit for palbociclib compares favorably: past trials showed that aromatase inhibitor treatment was associated with a 10-13 month PFS benefit.

Historically in breast cancer, overall survival has been a major criteria for approval by the U.S. Food and Drug Administration especially given the narrow PFS benefit observed with some agents in this disease. Based on the immature OS results from PALOMA-1, it is unclear if palbociclib will be able to achieve a significant survival advantage. The discussant Dr. Baselga noted caution on accepting the PFS benefits from Phase II data based on recent failures with most recent example of iniparib that failed in Phase III trials following impressive Phase II benefit. Given the small sample size and the aggressive nature of breast cancer,  it might be ideal to await the results of ongoing Phase III PALOMA-2 study (NCT01740427) of palbociclib plus letrozole as first-line therapy or the Phase III PALOMA-3 study (NCT01942135), which is comparing the addition of palbociclib to faslodex in later lines of therapy.

Dr. Baselga acknowledged the difficulty for Pfizer as they make this this decision, when he noted some of the competition for palbociclib. Eli Lilly’s CDK 4/6 inhibitor bemaciclib (LY2835219) recently presented phase I data in breast cancer patients, and will be examined in a phase II trial in HR+, HER2- patients (NCT02102490). Also, Novartis has recently reported Phase I data for their CDK 4/6 inhibitor LEE011 (Infante, 2014 International Congress on Targeted Anticancer Therapies) that was evaluated in a dose-escalation study in 78 patients with solid tumors. Although the trial had only five breast cancer patients, LEE011 as a monotherapy achieved two partial responses and was well-tolerated. This phase I data supported Novartis’ Phase III trial (MONALEESA-2; CLEE011A2301; NCT01958021) which will evaluate the efficacy of LEE011 in combination with letrozole. Finally, Novaris’s PI3K inhibitor buparlisib (BKM120) is the subject of two phase III trials [BELLE-2 (NCT01610284); BELLE-3 (NCT01633060)] for HER2-positive patients.  This competition highlights Pfizer’s quandary.  If they choose (or the FDA forces them to choose) to wait, they stand a chance of losing their first-to-market advantage. However, it is also hard to ignore such a striking PFS benefit in this patient population. After all, Afinitor® (everolimus, Novartis) was approved in the relapsed/refractory HER2- postmenopausal setting based on a 6-month PFS benefit.

No matter what happens next for now, it seems CDK inhibitors have gained a slot in physician’s arsenal of options for the treatment of HR+ metastatic breast cancer.  Kantar Health eagerly awaits to hear Pfizer’s future plans for palbociclib.

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by Neesha Suvarna, Ph.D., Consultant, Kantar Health and Arnold DuBell, Ph.D., M.B.A., Consultant, Kantar Health

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