Immuno-Oncology:
Harnessing the Oncologist
That Lies Within A Patient’s
Immune System
Kevin P. Hubbard, DO, FACOI
Interim Chair - Department of Specialty
Medicine
Professor and Chair - Division of Internal
Medicine
Kansas City University of Medicine and
Biosciences - College of Osteopathic Medicine
Financial Disclosures
I have no real or apparent conflict of interest with the information presented
in this lecture
Introduction
Immuno-Oncology Concepts
The immune system
Cancer-immunity relationships
http://www.medscape.org/viewarticle/844988
http://www.medscape.org/viewarticle/844988
http://www.medscape.org/viewarticle/844988
http://www.medscape.org/viewarticle/844988
Immuno-Oncology Concepts
The immune system
Cancer-immunity relationships
http://www.medscape.org/viewarticle/844988
http://www.medscape.org/viewarticle/844988
http://www.medscape.org/viewarticle/844988
http://www.medscape.org/viewarticle/844988
http://www.medscape.org/viewarticle/844988
http://www.medscape.org/viewarticle/844988
http://www.medscape.org/viewarticle/844988
http://www.medscape.org/viewarticle/844988
New Treatments for Melanoma
Historically, a fatal disease once distant metastasis
occurs
Typically radiation resistant, and chemotherapy
regimens minimally effective (15-35% in most
series)
Immune response modifiers (IL-2, α-interferon)
offered modest benefit (10-40%) but with improved
progression-free survival compared to cytotoxics
New Treatments for Melanoma
As a result of several trials, therapies targeting key
biochemical pathways have led to new agents with
improved responses and more modest toxicities
Additionally, agents focused on improving the
immune response have demonstrated efficacy in the
disease
New Treatments for Melanoma
Ipilimumab (Yervoy®)
Monoclonal antibody directed at the
cytotoxic T-lymphocyte-associated
protein 4 (CTLA-4)
CTLA-4 is involved with immune
activity as a “checkpoint”
Ipilimumab inhibits CTLA-4, which
activates cytotoxic T cells, initiating a
cellular response to melanoma
(checkpoint inhibition)
New Treatments for Melanoma
Ipilimumab (Yervoy®)
Monoclonal antibody directed at the
cytotoxic T-lymphocyte-associated
protein 4 (CTLA-4)
CTLA-4 is involved with immune
activity as a “checkpoint”
Ipilimumab inhibits CTLA-4, which
activates cytotoxic T cells, initiating a
cellular response to melanoma
(checkpoint inhibition)
New Treatments for Melanoma
Ipilimumab (Yervoy®)
FDA approved for treatment of metastatic
melanoma
Improves overall survival
Change in “typical” response to
treatment…sometimes note increase in tumor size
prior to regression of disease (“pseudoprogression”)
New Treatments for Melanoma
If oncologists can’t use established
criteria for response, what will they
do?
“you gotta know when to hold ‘em,
and know when to fold ‘em…”
~Kenny Rogers
http://www.medscape.org/viewarticle/830449
New Treatments for Melanoma
Ipilimumab (Yervoy®)
Toxicities: many are auto inflammatory and due to cytokine
release
Colitis (8-23%)
Hypophysitis (1-5%)
Hepatitis (3-7%)
Pneumonitis (variable, but almost always <5%)
Skin eruptions (0-4%)
New Treatments for Melanoma
Antibodies targed at PD-1/PD-L1
Nivolumab (PD-1)
Pembrolizumab (PD-1)
PD-L1 targeted antibodies coming soon!
Antibodies Targeted at PD-1
Keynote 002 Trial (Ribas A, et al.; Lancet Oncol 2015; Jun 23. pii: S1470-2045(15)00083-2)
540 patients with ipilimumab-refractory advanced
melanoma (and BRAF directed treatment in patients with a
BRAF V600 mutation) randomly assigned to pembrolizumab
(2 mg/kg every three weeks), pembrolizumab (10 mg/kg
every three weeks) or chemotherapy (carboplatin plus
paclitaxel, paclitaxel alone, dacarbazine, or temozolomide
per institutional standard)
Treatment continued until disease progression
Antibodies Targeted at PD-1
Keynote 002 Trial (Ribas A, et al.; Lancet Oncol 2015; Jun 23. pii: S1470-2045(15)00083-2)
Chemotherapy
(control group)
Pembrolizumab
2mg/kg
Pembrolizumab
10 mg/kg
Progression-free
survival (hazard
ratio)
-
0.57
(95% .45-.73;
p<.0001)
.50
(95% CI .39-.64;
p<.0001)
Progression-free
survival (6-month)
16%
34%
38%
Grade 3-4 Toxicity
26%
11%
14%
Antibodies Targeted at PD-1
Nivolumab
Previously untreated patients → Checkmate 066
Trial (Robert C; et al.; N Engl J Med. 2015;372(4):320)
418 previously untreated patients with wild type
BRAF melanomas randomly assigned to
nivolumab (3 mg/kg every two weeks) or
dacarbazine (1000 mg/m2 every three weeks)
Antibodies Targeted at PD-1
Checkmate 066 Trial (Robert C; et al.; N Engl J Med. 2015;372(4):320)
Dacarbazine
Nivolumab
Response Rate
14%
40%
Duration of Response
(months)
2.2
5.1
12-month Response Rate
42%
73%
(HR) for death 0.42, 99.8% CI 0.25-0.73
Antibodies Targeted at PD-1
Nivolumab
Previously treated patients → Checkpoint 037 trial (Weber JS, et. al.; Lancet Oncol.
2015;16(4):375)
405 patients with prior anti-CTLA4 therapy (and BRAF directed treatment
in patients with a BRAF V600 mutation) randomly assigned in a 2:1 ratio
to either nivolumab or chemotherapy (either dacarbazine or carboplatin
plus paclitaxel)
Results of planned interim analysis are based upon 167 patients (120
treated with nivolumab and 47 treated with chemotherapy) with a
minimum follow-up of ≥6 months
Antibodies Targeted at PD-1
Checkpoint 037 trial (Weber JS, et. al.; Lancet Oncol. 2015;16(4):375)
Chemotherapy
Nivolumab
Response Rate
10%
32%
Median Duration of
Response (months)
3.5
Not yet reached at time of
analysis
Tumor responses were seen with nivolumab in patients with BRAF mutations who
had progressed on a prior BRAF inhibitor (6/26 = 23%) and appeared to be
independent of benefit from prior ipilimumab treatment
Current Management of Melanoma
The role of PD-1 directed therapies has
revolutionized treatment of this disease
Emerging data sets suggest improved responses to
multiagent therapies (PD-1 plus CTLA-4 or PD-1
plus BRAF or MEK inhibition)
Newer Approaches in NSCLC
Patients with Stage I, II, or III NSCLC are generally treated with
curative intent using surgery, chemotherapy, radiation therapy
(RT), or a combined modality approach
Factors affecting choice of treatment
Extent of disease
Characterization of the tumor (histology, driver mutation
status)
Patient-specific issues (age, co-morbidities, performance
status)
Newer Approaches in NSCLC
Systemic therapy options
Cytotoxic chemotherapy
Targeted agents
Monoclonal antibodies
Choices depend on molecular and histologic features of the tumor,
presence of a driver mutation
Age of patient factors in as well (older patients are less well
studied)
Newer Approaches in NSCLC
“Driver mutation” — occur in
cancer cells with mutations in
genes encoding for proteins
critical to cell growth and
survival
Typically not found in the
germ line (normal) cells,
thus allows for targeting of
malignant cells
Immunotherapy in Lung Cancer???
For many years, bronchogenic carcinoma not
considered immunogenic
Phase I study of nivolumab in previously treated
NSCLC (Raez LE, et al. Clin.Med. Res. 2005. 3:221-228) )
Nivolumab - fully human PD-1 monoclonal antibody
Overall response 18%, OS 9.9 months, 1-year
survival 42%
Immunotherapy in Lung Cancer???
Phase 2 study of nivolumab in refractory squamous
cell NSCLC demonstrated 14.5% overall response
rate (Topalian SL, Hodi FS, Brahmer JR. New Engl Jour Med 2012; 366:2443)
Durable responses noted, lasting several months
Most patients treated with conventional therapy who
respond have a response duration of a few weeks
Immunotherapy in Lung Cancer???
http://www.medscape.org/viewarticle/844988
Improved response and overall survival vs docetaxel
Immunotherapy in Lung Cancer???
As a result of this data, the US Food and Drug
Administration granted approval on March 4, 2015 of
nivolumab for the treatment of patients with
advanced squamous NSCLC with progression on or
after platinum-based chemotherapy
Immunotherapy in Lung Cancer???
Pembrolizumab→KEYNOTE 001 Trial (Geron EB, et al.; N Engl J Med 2015; 372:20182028)
Phase I trial of 495 patients receiving pembrolizumab at a dose of
either 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2
weeks
Assigned to either a training group (182 patients) or a validation
group (313 patients)
PD-L1 expression in tumor samples assessed using
immunohistochemical analysis, with results reported as the
percentage of neoplastic cells with staining for membranous PD-L1
(proportion score)
Immunotherapy in Lung Cancer???
KEYNOTE 001-Results (all patients on treatment) (Geron EB, et al.; N Engl J Med 2015;
372:2018-2028)
Objective response rate 19.4%
Median duration of response 12.5 months
Median duration of progression-free survival 3.7 months
Median duration of overall survival 12 months
PD-L1 expression in at least 50% of tumor cells correlated with improved
efficacy→ORR in that group was 45.2% median overall survival not reached
at time of data analysis
Immunotherapy in Lung Cancer???
Toxicities to PD-1/PD-L1 therapies
General: fatigue, rash, pruritis, myalgias, loss of
appetite
On occasion: colitis, thyroiditis, elevation of liver
transaminases, autoimmune disorders
Points to Remember…
Most cancers stimulate the immune system
Therapeutic immunity can be either passive or
active
Passive = supplying an antibody response
Active = vaccination to achieve an antibody
response
Therapeutic approaches now available can stimulate
immunity and address mechanisms of immune
What’s Coming Down The Pike?
Beyond melanoma and NSCLC, CTLA-4-and PD-1-directed
therapies are being evaluated for the treatment of prostate
cancer, renal cell carcinoma, breast cancer, bladder cancer,
colorectal cancer, gastric cancer, and hematologic
malignancies
The use of CTLA-4 and PD-1-directed therapies are being
explored in combination with conventional chemotherapy in a
wide variety of malignancies, including NSCLC, melanoma,
breast cancer, and prostate cancer
Conclusions
There is a close relationship between the immune
system and cancer control, growth, and metastasis
Novel therapies targeting these relationships are being
developed for a wide variety of malignancies, and hold
promise for effective treatment and manageable side
effects
The role of PD-1/PD-L1 and CTLA-4 directed therapies in
combination with other modalities is still being explored
things are changing
quickly…
Stay Tuned!!!
Questions?