"Guarded Optimism" after Phase 2 trial results for novel drug against (HER2-negative ER-positive) breast cancer

The American Association for Cancer Research (AACR) is holding its annual meeting this year in San Diego. There have been many exciting developments, but perhaps the biggest was by the pharmaceutical company Pfizer which reported the Phase 2 clinical trial results of its anti-breast cancer drug Palbociclib. One cancer researcher proclaimed that the results were “quite groundbreaking.” The title of the New York Times article on the results was a bit more subdued: "Guarded Optimism After Breast Cancer Drug Shows Promising Results". I think guarded optimism is the better description.

Palbociclib works by inhibiting cyclin-dependent kinases 4 and 6 (Cdk 4/6) which are involved in regulating the cell cycle. Normal cells have typically differentiated into specialized cells that no longer divide; cancer cells have an abnormal cell cycle that allows them to continue to divide. Blocking Cdk 4/6 can prevent cell division in tumor cells.

One of the most effective chemotherapeutic agents against breast cancer is Herceptin which is an antibody against the Her2 receptor. While it is very effective against tumor cells that contain the receptor, it is ineffective against tumors that lack the receptor (Her2-negative) which constitute the majority of breast cancers (75%). Palbociclib can work against Her2-negative tumors. In the study, the target patient population possessed ER-positive (contained estrogen receptor) Her2-negative tumors, which represents about 60-65% of breast cancers.

Last year Pfizer reported the interim results from this Phase 2 trial, and showed that the difference in median progression-free survival was 26.1 months for Palbociclib versus 7.5 months for the control group. Progression-free survival represents the length of time in which the breast cancer did not get worse. All women in the trial (both Palbociclib and control) took Letrozole, a drug that blocks the synthesis of estrogen, which is the standard of care.

The good news is that this preliminary result held up although the difference from the control decreased. In the completed Phase 2 trial, the median progression-free survival was 20.2 months for those who received Palbociclib, compared to 10.2 months for the control group, which was statistically significant.

The bad news was that the drug did not prolong overall survival by a statistically significant amount. Those who received Palbociclib lived a median of 37.5 months compared with 33.3 months for the control group (Figure 1), which was within the margin of error for the trial (p < 0.21, HR = 0.81).

How does one reconcile these two seemingly conflicting results? The optimistic interpretation is that many in the Palbociclib progression-free survival group have not yet died (i.e. overall survival counts only those who have died), and that ultimately they will live longer than those still alive in the control group, thus increasing the median overall survival difference. The pessimistic interpretation is that many in the Palbociclib progression-free survival group will relapse and then die quickly so that their survival may not exceed that of the control. A likely scenario is that something in between will happen; I suspect that there will be a significant overall survival effect, but not twice as long as in the progression-free data.

The Phase 3 trials (with a much larger patient population and a longer observation time) will allow a more thorough evaluation. Let us hope for the best.

Figure 1. Overall survival curves for Palbociclib + Letrozole (PAL+LET, blue line) and Letrozole alone (LET control, yellow line).