How can immunotherapy be used to treat metastatic breast cancer? Ian Krop, MD, PhD, discusses the latest research and treatment options.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held on October 17 and hosted by the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute in Boston, Mass.
For more information, visit www.susanfsmith.org
12. Antibodies to PD-1 or PD-L1 prevent
tumor cells from inactivating T-cells
13.
14. Antibodies to PD-1 shrinks cancers in the
majority of patients with metastatic melanoma
15. Scott N. Gettinger et al. JCO doi:10.1200/JCO.2014.58.3708
Antibodies to PD-1 are effective in patients with
advanced lung cancer
16. Why such durable responses in very
advanced cancers?
• Immune system targets many parts of the
cancer (antigens)
– Harder for cancer to escape recognition
• Advanced cancers’ frequent mutations make
them more “foreign” to immune system
18. Immune therapy in triple negative
cancers
• Highest rate of PD-L1 expression
• Highest rate of mutations
• High level of immune cells in the tumor
(TILS)
19. This presentation is the intellectual property of the presenter, Rita Nanda. Contact rnanda@medicine.bsd.uchicago.edu for permission to reprint and/or distribute.
December 9-13, 2014
A Phase Ib Study of Pembrolizumab
(MK-3475) in Patients With Advanced
Triple-Negative Breast Cancer
Rita Nanda,1 Laura Q. Chow,2 E. Claire Dees,3 Raanan Berger,4 Shilpa Gupta,5
Ravit Geva,6 Lajos Pusztai,7 Marisa Dolled-Filhart,8 Kenneth Emancipator,8
Edward J. Gonzalez,8 Jennifer Pulini,8 Kumudu Pathiraja,8 Vassiliki Karantza,8
Gursel Aktan,8 Christine Gause,8 Jonathan Cheng,8 Laurence Buisseret9
1University of Chicago, Chicago, IL; 2University of Washington, Seattle, WA;
3University of North Carolina Lineberger Cancer Center, Chapel Hill, NC;
4Sheba Medical Center, Tel Hashomer, Israel; 5H.Lee Moffitt Cancer Center and Research Institute, Tampa, FL;
6Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; 7Yale University School of Medicine, New Haven, CT;
8Merck & Co., Inc., Whitehouse Station, NJ; 9Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium
20. This presentation is the intellectual property of the presenter, Rita Nanda. Contact rnanda@medicine.bsd.uchicago.edu for permission to reprint and/or distribute.
December 9-13, 2014
Change From Baseline in Target Lesions Over Time
(Central Review)
-100
-80
-60
-40
-20
0
20
40
60
80
100
0 8 16 24 32 40 48 56
ChangeFromBaseline,%
Time, weeks
Analysis cut-off date: November 10, 2014.
On treatment
Discontinued treatment
21. Emens LA, et al. AACR, 2015.
Inhibition of PD-L1 by MPDL3280A leads to
clinical activity in patients with
metastatic triple-negative breast cancer (TNBC)
Leisha A. Emens,1 Fadi S. Braiteh,2 Philippe Cassier,3 Jean-Pierre DeLord,4
Joseph Paul Eder,5 Marcella Fassò,6 Yan Wang,6 Wei Zou,6 Luciana Molinero,6
Daniel S. Chen,6 Ian Krop7
1Johns Hopkins University, Baltimore, MD; 2Comprehensive Cancer Centers of Nevada, Las Vegas, NV;
3Centre Leon Berard, Lyon, France; 4Institut Claudius Regaud, Toulouse, France;
5Yale School of Medicine, New Haven, CT; 6Genentech, Inc., South San Francisco, CA;
7Dana-Farber Cancer Institute, Boston, MA
21
22. Emens LA, et al. AACR, 2015.
MPDL3280A: Tumor Burden Over Time
Efficacy-evaluable population with TNBC
22
• Median duration of response has not yet been reached (range: 18 to 56+ wks)
• Median duration of survival follow-up is 40 wks (range: 2+ to 85+ wks)
Investigator-assessed confirmed ORRs per RECIST v1.1.
Efficacy population includes patients dosed by July 21, 2014; clinical data cutoff, December 2, 2014.
New lesions at consecutive visits for the same patient might be the same lesion.
CR/PR (n = 4)
SD (n = 3)
PD (n = 9)
23. What do these trials tell us?
• Provides proof that immunotherapy can work
in breast cancer
• Important to note that:
– Only patients with PD-L1 positive TNBC were
included
– Only a minority of these patients benefited
24. Other immunotherapy targets in development
Activating Inhibiting
Mellman et al. Nature, 2011
Ipilimumab
Pembrolizumab
Nivolumab
25. FIRST LINE TNBC
Protocol # Short Title
15-241 Phase 3 Abraxane +/- Atezolizumab (anti-PDL1)
15-307 Phase 1/2 Eribulin + Pembrolizumab (anti-PD1)
SECOND LINE TNBC
15-240 Phase 2 Pembrolizumab Monotherapy
15-307 Phase 1/2 Eribulin + Pembrolizumab (anti-PD1)
Immunotherapy Trials for triple negative
breast cancer
26. Immunotherapy in other breast cancer
subtypes
• HER2+
– Modest PD-L1 expression
– Moderate/high mutational load
– Combination of PD-L1 inhibitor and HER2-antibodies
are effective in lab studies
• ER+
– Low PD-L1 expression
– Low mutational load
– Likely will need something to increase recognition by
immune system
27. Immunotherapy in other breast cancer
subtypes
• HER2+
– Modest PD-L1 expression
– Moderate/high mutational load
– Combination of PD-L1 inhibitor and HER2-antibodies
are effective in lab studies
• ER+
– Low PD-L1 expression
– Low mutational load
– Likely will need something to increase recognition by
immune system
29. Immunotherapy in Breast Cancer: Summary
• Great promise… in other malignancies
– Melanoma, lung cancer, lymphoma
• Data in breast cancer is very early
– Pretreated phase 1 TNBC - exciting data
– Larger trials underway
– MANY questions remain:
• Is PDL1+ prerequisite for activity?
• Will benefit be found in TNBC only, or in other subtypes?
• Do we need to use drugs targeting other pathways
• Much more data in next few years in breast
cancer
Editor's Notes
Its been 50 years since one fo the first observations of the compex interplay between cancer and the immune system
Clinical activity in patients with non–small-cell lung cancer (NSCLC) receiving nivolumab. Kaplan-Meier curves of overall survival (OS) for (A) total patient population (N = 129) and (B) patients who received nivolumab 1 (n = 33), 3 (n = 37), or 10 mg/kg (n = 59). Symbols indicate censored events, defined for OS as time to last known date alive before date of data analysis, for patients without death. (C) Tumor burden kinetics in patients with NSCLC treated with nivolumab 3 mg/kg (n = 37). Baseline tumor measurements are standardized to zero. Tumor burden was measured as sum of longest diameters of target lesions compared with baseline. Red triangles indicate first occurrence of new lesion. Horizontal dashed line at −30% indicates threshold for defining objective response (partial tumor regression) in absence of new lesions or nontarget disease progression, according to RECIST (version 1.0); vertical dashed line at 96 weeks indicates protocol-defined maximum duration of continuous nivolumab therapy. (D) Characteristics of objective responses in patients with squamous cell histology (n = 9) and nonsquamous cell histology (n = 13) treated with nivolumab. Vertical dashed line at 22 months indicates maximum planned duration of continuous nivolumab therapy. Eighteen responders discontinued nivolumab therapy for reasons other than disease progression, including: completion of maximum cycles (n = 7), adverse events (n = 8), withdrawal of consent (n = 2), and other (n = 1).