First-line treatment with the combination of palbociclib plus letrozole extended progression-free survival by approximately 50% in patients with metastatic estrogen receptor–positive, HER2-negative breast cancer, according to final results of the PALOMA-1 trial, a randomized phase II study presented at the American Association for Cancer Research (AACR) Annual Meeting 2014 in San Diego.

Palbociclib plus letrozole achieved progression-free survival of 20.2 months vs 10.2 months with letrozole alone (P = .0004). Overall survival was trending in favor of the combination but was not statistically significant at the time of the progression-free survival analysis.

“These data give us the confidence to move ahead with a phase III study. To put the data in perspective, no study of aromatase inhibitors alone in metastatic breast cancer showed as dramatic a progression-free survival improvement as this study,” said presenting author ­Richard S. Finn, MD, Associate Professor of Medicine, Geffen School of Medicine at the University of California, Los Angeles. Dennis Slamon, MD, PhD, Professor of Medicine and Director of the Revlon/UCLA Women’s Cancer Program, was the senior author.

Palbociclib, being developed by Pfizer, Inc, is a first-in-class cyclin-dependent kinase (CDK) 4/6 inhibitor that inhibits cell proliferation and cellular DNA synthesis by preventing cell-cycle progression. Other companies are also pursuing CDK4 and CDK6 inhibitors in breast cancer, including Lilly (with LY2835219) and Novartis (with LEE011).

Phase II Study

The phase II study presented at the AACR Annual Meeting consisted of two parts. Part 1 randomly assigned 66 postmenopausal patients with estrogen receptor–positive, HER2-negative, locally recurrent or metastatic breast cancer to the combination of palbociclib plus letrozole or letrozole alone. Part 2 randomly assigned an additional 99 patients to the same treatment arms with the same tumor characteristics as well as two additional potential biomarkers: CCND1 amplification and/or loss of p16.

In part 1, progression-free survival was 26.1 months for the combination of palbociclib plus letrozole vs 5.7 months for letrozole alone (P < .0001). In part 2, progression-free survival was 18.1 vs 11 months, respectively (P = .0046).

Dr. Finn called attention to progression-free survival in the control arms of part 1 and 2, noting that the population enriched for CCND1 amplification and loss of p16 “behaved differently” with letrozole alone. Overall, he continued, the take-away message from this study is that estrogen receptor positivity is the most sensitive predictor of response to the novel agent in combination with letrozole.

Best overall response rate was 43% for the combination vs 33% for letrozole alone. Clinical benefit rate (complete and partial response plus stable disease) was 81% vs 58%, respectively.

Subgroup analysis showed that the progression-free survival benefit for the combination was consistent across all subgroups, including age, sites of metastatic disease, and previous adjuvant therapies or no adjuvant therapy.

Overall survival at this early time point was 37.5 months for the combination vs 33.3 months with letrozole alone. This difference was not statistically significant.

Acceptable Toxicity

The toxicity of palbociclib in combination with letrozole was acceptable. Adverse events associated more frequently with the combination than with letrozole alone included neutropenia (grade 3, 48%, grade 4, 6%), leukopenia (grade 3, 19%), fatigue, and anemia.

At the end of the trial, 23% of patients treated with palbociclib plus letrozole remained on therapy vs 10% on letrozole alone. The most common reason for treatment discontinuation was disease progression.

“These data with palbociclib plus letrozole are impressive, and if confirmed in a larger phase III trial, will offer an additional alternative to breast cancer patients with receptor-positive metastatic disease similar to the excitement that resulted with early trials of everolimus and letrozole. If the palbociclib preliminary data are confirmed in phase III trials and remain as impressive, our patients will yet have another therapeutic alternative,” commented Patricia LoRusso, DO, Director of the Center for Experimental Therapeutics at the Barbara Ann Karmanos Center in Detroit. Dr. LoRusso moderated the press conference where these results were presented.

Dr. Slamon said “The potential impact of this study could be huge. We are doing further phase III work [PALOMA-2] with the drug, but the current data are as exciting as the initial studies we were involved in when testing trastuzumab (Herceptin) for HER2-positive breast cancers.” Palbociclib has been granted Breakthrough Therapy designation by the FDA for first-line therapy of estrogen receptor–positive, HER2-negative advanced breast cancer. ■

Disclosure: Drs. Finn and LoRusso reported no potential conflicts of interest. Dr. Slamon has received honoraria from Genentech and Sanofi-Aventis.

Reference

1. Finn RS, et al: AACR Annual Meeting. Abstract CT101. Presented April 6, 2014.