Breast Cancer Pioneer Examines Novel Therapies for Metastatic Breast Cancer

Dennis Slamon, MD, PhD

The inhibition of CDK 4/6 and PD-1 represent two of the most exciting developments in the field of metastatic breast cancer. Following an accelerated approval in February 2015, the CDK4/6 inhibitor palbociclib (Ibrance) has continued to make headlines as an exciting new agent for patients with HR-positive metastatic breast cancer. Additionally, PD-1 and PD-L1 inhibitors have shown early signs of promise for patients with metastatic triple-negative breast cancer (TNBC).

The phase II PALOMA-1 trial,¹ which was the basis for the approval of palbociclib, found that the novel CDK 4/6 inhibitor in combination with letrozole (Femara) reduced the risk of disease progression by 51% compared with letrozole alone. The median progression-free survival (PFS) with palbociclib was 20.2 versus 10.2 months for letrozole alone (HR, 0.488; P = .0004).

At the 2015 ASCO Annual Meeting, the PALOMA-3 trial found that palbociclib plus fulvestrant (Faslodex) improved PFS compared with fulvestrant alone in women with HR-positive, HER2-negative metastatic breast cancer following progression on prior endocrine therapy.² At the time of the interim analysis, the median PFS was 9.2 months for palbociclib plus fulvestrant and 3.8 months for placebo plus fulvestrant (HR, 0.422; 95% CI, 0.318-0.560; P <.0001).

In addition to this now FDA-approved approach, two early phase clinical trials have shown potential for PD-1/PD-L1 inhibition in pretreated patients with TNBC. In the KEYNOTE-012 trial,³ pembrolizumab demonstrated an overall response rate (ORR) of 18.5%. In a similar patient population, the PD-L1 inhibitor atezolizumab showed an ORR of 19%.⁴ Larger trials are now looking to confirm these findings.

OncLive: What was the rationale for investigating CDK 4/6 inhibition in hormone receptor-positive breast cancer?

For more information on CDK 4/6 inhibition and the future of PD-1 in breast cancer, OncLive spoke with the 2014 Breast Cancer Giant of Cancer Care Dennis Slamon, MD, PhD, director of Clinical/Translational Research, and director of the Revlon/UCLA Women's Cancer Research Program at UCLA's Jonsson Comprehensive Cancer Center.Slamon: The rationale was really based on the preclinical data that was generated in the laboratory. One of the exciting things about being at UCLA is that we have a pretty good track record of translating things out of the lab into the clinic with real impact.

Can you discuss the potential of palbociclib for women with untreated ER-positive, HER2-negative metastatic breast cancer?

In what setting does palbociclib have the most potential?

What were the most important findings from the PALOMA-3 trial?

The current approved indication is for patients who have progressed on hormonal therapy. I think it is also going to be looked at in early breast cancer and is going to be added to hormonal therapy upfront. That needs to be tested in the clinical setting and those trials are planned or are just starting, so it will take a little while to get the results. I am encouraged by what I’ve seen in the laboratory and what we’ve seen in the clinic with later stage patients. The PALOMA-3 trial showed us that CDK 4/6 inhibition when combined with fulvestrant, a whole different approach to hormonal blockade, was equally as effective to what we saw with letrozole. The preclinical data that we generated that got these trials launched demonstrated that the drug would work with tamoxifen, with aromatase inhibitors, or with fulvestrant almost equally. It was great to see the clinical data confirm that.

Looking forward to other approaches, what is on the horizon for immunotherapy in breast cancer?

How do you see the role for PD-1 inhibition evolving?

It was irrelevant what type of anti-hormonal therapy was used in combination with the CDK 4/6 therapy. Preclinically we got the same impact with all three combinations, and at least for two of the three combinations so far the same is true in the clinic. There seems to be little doubt that the anti—PD-1 therapies will evolve in breast cancer. There are some very early data in triple-negative breast cancer that looks very promising. I think that is going to be explored, but I would be surprised if it were restricted just to those groups. The PD-1 story has really been an exciting story. We’ve learned that perhaps one of the things that has been holding back immunotherapy for a long time has been checkpoints. Clearly, the data that has come out of melanoma and lung cancer is very encouraging, but these advances will not be restricted to just those two cancers. Immunotherapy does not have a role in all cancers but I think it will make a meaningful impact for a lot of patients.

References

1. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2- negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study [published online December 16, 2014]. Lancet Oncol. 2015;16(1):25-35.
2. Turner N, Ro J, Andre F, et al. PALOMA3: A double-blind, phase III trial of fulvestrant with or without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy. J Clin Oncol. 33;2015 (suppl; abstr LBA502).
3. Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Paper presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S1-09.
4. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract 6317.

We screened a CDK 4/6 inhibitor in our preclinical breast cancer panel, looking for activity. What we saw was hormone receptor-positive breast cancers appeared to have profound sensitivity to the drug palbociclib. That led to designing and implementing a phase I study to test the drug in that population in combination with hormonal therapy. That ultimately led to the phase II trial that got the drug approved and the phase III confirmatory trial.The data that came out that got everyone excited was that palbociclib was so impactful in HER2-negative, ER-positive patients that had progressed either while on hormone therapy or after adjuvant hormone therapy. Palbociclib combined with letrozole and also palbociclib combined with fulvestrant which have both been investigated in trials we have been involved in, are both compelling combinations. When palbociclib is combined with standard therapy it makes a huge impact and potentially doubles PFS. That is a significant improvement in PFS. Now we are looking at the impact of overall survival.